Novel Sulfonamide TRPA1 Receptor Antagonists

ABSTRACT

The invention discloses compounds of Formula (I). The compounds of formula (I) are TRPA1 antagonists and are useful as active ingredients of pharmaceutical compositions for the treatment of pain and other conditions ameliorated by the inhibition of TRPA1 receptors.

FIELD OF THE INVENTION

The present invention concerns TRPA1 antagonists characterized by novelsulfonamide or cyclopropyl sulfonamide moieties and, when possible,pharmaceutically acceptable salts thereof along with the formulationscontaining them. The pharmaceutical compositions of the invention areuseful in the treatment of pain, pulmonary diseases and other conditionsameliorated by the inhibition of the TRPA1 receptors.

BACKGROUND OF THE INVENTION

TRPA1 (ANKTM1, p120) is a non-selective cation channel that belongs tothe Transient Receptor Potential (TRP) superfamily. TRPA1 was firstidentified as a transformation sensitive mRNA in cultured human lungfibroblasts (Jaquemar et al., J. Bio. Chem., 1999, 274, 7325-7333).Subsequent studies indicated that TRPA1 is also highly expressed insensory neurons of the dorsal root, trigeminal and nodose ganglia aswell as in hair cells of the inner ear (Story et al., Cell, 2003, 112,819-829; Corey et al., Nature, 2004, 432, 23730; Nagata et al., JNeurosci., 2005, 25, 4052-4061; Diogenes et al., J. Dent. Res., 2007,86, 550-555). In sensory neurons, TRPA1 expression is most abundant insmall diameter neurons where it co-localizes with markers of peptidergicnociceptors such as TRPV1, CGRP and substance P (Story et al., supra;Bautista et al., PNAS, 2005, 102, 12248-12252; Nagata et al., J.Neurosci., 2005, 25, 4052-4061; Diogenes et al., J. Dent. Res., 2007,86, 550-555).

The finding that TRPA1 is expressed in small diameter nociceptors hasled to the suggestion that this channel may be involved in painsensation. Indeed a number of additional observations support thissuggestion. For example, TRPA1 expression is increased by inflammatorymediators such as NGF (Diogenes et al., J. Dent. Res., 2007, 86,550-555) and following nerve injury or inflammation (Obata et al., J.Clin. Invest. 2005, 115, 2393-2401; Frederick et al., Biochem. Biophys.Res. Commun., 2007, 358, 1058-1064). Bradykinin, a potent algogenicpeptide released at sites of injury and inflammation, activates TRPA1via G-protein coupled BK2 receptors (Bandell et al., Neuron, 2004, 41,849-857). In addition, TRPA1 is activated by a range of pungent orirritant compounds per se eliciting pain in animals and humans, such asmustard oil (AITC), cinnamaldehyde, acreolin, allicin, and formalin(Bandell et al., supra; Namer et al., Neuroreport, 2005, 16, 955-959;Bautista et al., Cell, 2006, 124, 1269-1282; Fujita et al., Br. J.Pharmacol., 2007, 151, 153-160; McNamara et al., PNAS, 2007, 104,13525-13530).

Finally, TRPA1 may also be activated by noxious cold (Bandell et al.,Neuron, 2004, 41, 849-857; Jordt et al., Nature, 2004, 427, 260-265;Nagata et al., J. Neurosci., 2005, 25, 4052-4061) and the intra-thecaladministration of TRPA1 anti-sense oligodeoxynucleotide suppressesinflammation as well as nerve injury, induced cold allodynia (Obata etal., J. Clin. Invest., 2005, 115, 2393-2401). Likewise, mustard oil andbradykinin-induced acute pain and hyperalgesia is abolished inTRPA1−/−mice (Bautista et al., supra; Kwan et al., Neuron, 2006, 50,277-289).

TRPA1 receptors also play a role in airway disorders. Treatment withcigarette smoke extracts (CSE) increases Ca²⁺ influx inTRPA1-transfected cells, and promotes neuropeptide release from isolatedguinea pig airway tissue. Furthermore, the effect of CSE on Ca²⁺ influxin dorsal root ganglion neurons is abolished in TRPA1-deficient mice.These data suggest a role for TRPA1 in the pathogenesis of CSE-induceddiseases such as chronic obstructive pulmonary disease (COPD) (Andre etal., J. Clin. Invest., 2008, 118, 2574-2582).

Recent data highlighted the TRPA1 channel role in inflammation andbronchial hypereactivity in a murine asthma model. Other studiesprovided evidence that inhalation of TRPA1 stimulants elicited coughreflex in guinea pigs and human volunteers. (Facchinetti et Patacchini,The Open Drug Discovery J. 2010, 2, 71-80). TRPA1 antagonists couldemerge as novel drugs for treatment of COPD, asthma and chronic cough.

TRPA1 is found also in bladder and urethra urothelium, epithelium andnerve fibers of the urothelium, sub-urothelial space, muscle layers andaround blood vessels (Du et al., Urology, 2008, 72, 450-455; Andrade etal., Biochem. Pharmacol., 2006, 72, 104-114; Gratzke et al., Eur.Urology, 2008, Apr. 30 e-pub; Streng et al., Eur. Urology, 2008, 53,391-400). TRPA1 expression is increased in bladder mucosa from patientswith bladder outlet obstruction (Du et al., Urology, 2008, 72, 450-455).Activation of TRPA1 increases micturition frequency and reduces voidingvolume (Streng et al., supra).

Activation of TRPA1 in the bladder by reactive metabolites ofcyclophosphamide (e.g., acrolein) may be responsible for cystitis thatsometimes accompanies the use of chemotherapeutic agents (Bautista etal., supra). TRPA1 is also expressed in colonic afferents, isupregulated following induction of experimental colitis, and TRPA1antisense oligonucleotides suppresses colitis-induced hyperalgesia tocolonic distension (Yang et al., Neurosci Lett., 2008, 440, 237-241).These data suggest a role for TRPA1 in the pathogenesis of visceral painand dysfunction, such as bladder instability, urinary incontinence,cystitis and colitis.

DESCRIPTION OF THE INVENTION

The present invention relates to TRPA1 inhibitors of formula (I)

wherein:

Ar₁ is:

i) phenyl substituted with 0, 1, 2 or 3 substituents R_(a); or

ii) a 5- or 6-membered monocyclic aromatic heterocycle ring optionallysubstituted with one or two substituents R_(a); where each R_(a) isindependently halo, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CN, —CF₃, —OCF₃, —NO₂,—C(O)C₁₋₄alkyl or —CO₂H;

Ar₂ is:

i) phenyl substituted with 0, 1, 2 or 3 substituents R_(b); where eachR_(b) is independently halo, —C₁₋₄alkyl, —C(O)NR_(c)R_(d), —OC₁₋₄alkyl,—OC₀₋₄alkylCF₃, —CN, —CF₃, —OCF₂H, —NO₂, —NR_(c)R_(d),—S(O)₀₋₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl, S(O)(O)NH₂, —(CH₂)₀₋₂-morpholinyl,piperidin-1-yl, piperazinyl, said piperazinyl being optionallysubstituted with a methyl, or two R_(b) substituents on adjacent carbonatoms taken together form —O(CH₂)₁₋₂O—;

ii) pyridyl substituted with 0, 1 or 2 substituents R_(e); where eachR_(e) is independently selected from halo, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CF₃, —NR_(c)R_(d) or 4-morpholinyl; or

iii) a bicyclic 9-11-membered aromatic heterocycle optionallysubstituted with 1 substituent R_(f′); where R_(f) is —C₁₋₄alkyl;

R_(c) and R_(d) are each independently selected from H or —C₁₋₄alkyl;

R₁ is H, C₁₋₄alkyl-O—C₁₋₄alkyl, or C₁₋₄alkyl optionally substituted withhalo;

R₂, R₃, R₄, and R₅ are each independently H, halo or —C₁₋₄alkyl;

n is 0 or 1 providing that when n is 1 the bond between C1 and C2 issingle and when n is 0 the bond between C1 and C2 is double;

each Y₁, Y₂ and Y₃ is independently CH or N;

R₆ is

i) H, —C₁₋₄alkyl, —CF₃, —OR_(z) or —NR_(h)R_(i);

where R_(h) is selected from

a) H, —C₀₋₄alkylCF₃, —C₁₋₄alkyl-N(CH₃)₂, saturated C₃₋₇cycloalkyl or—C₁₋₄alkyl-monocyclic heteroaryl ring;

b) —C₁₋₅alkyl optionally substituted with OH;

c) —C₁₋₄alkyl-heterocycloalkyl, said heterocycloalkyl being optionallysubstituted with —C₁₋₄alkyl; or

d) —C₀₋₄alkyl-phenyl, said phenyl being optionally substituted with oneor two R_(j) moieties; where each R_(j) is independently halo,—OC₁₋₄alkyl,

R_(Z) is —C₁₋₄alkyl, —C₁₋₄alkylCF₃ or —C₁₋₄alkyl-heterocycloalkyl;

ii) 1-pyrrolidinyl optionally substituted with a moiety selected fromthe group consisting of —NR_(k)R_(i) and —C₁₋₄alkyl, said —C₁₋₄alkylbeing optionally substituted with —OH;

iii) 1-piperidinyl optionally substituted with —C₁₋₄alkyl, —C(O)NH₂,—CO₂C₁₋₄alkyl or —C₀₋₄alkyl-phenyl;

iv) piperazinyl optionally substituted with —C₁₋₅alkyl, —OC₁₋₄alkyl,—C₀₋₄alkylpyridyl, —C₀₋₄alkyl-1-methyl-piperidin-4-yl,—C₀₋₄alkylNR_(k)R_(i) or —C₀₋₄alkyl-phenyl, said phenyl optionallysubstituted with one or two R_(T) substituents; where each R_(T)substituent is selected from the group consisting of halo, —OCF₃,—C₁₋₄alkyl, —OC₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl and—C₀₋₄alkylNR_(k)R_(i), or two R_(T) substituents on adjacent carbonatoms taken together form —O(CH₂)₁₋₂O—;

v) phenyl optionally substituted with halo, —CF₃, —OCF₃;

vi) pyridyl;

vii) morpholin-yl;

R_(k) is H, —C₁₋₄alkyl or —C(O)₁₋₂C₁₋₄alkyl;

R_(i) is H or C₁₋₄alkyl.

When one asymmetrical carbon is present in a compound of the formula(I), such a compound may exist in optically active form or in the formof mixtures of optical isomers, e. g. in the form of racemic mixtures.The present invention refers to all optical isomers and their mixtures,including the racemic mixtures.

In a further aspect of the present invention, compounds of formula Ibearing a basic nitrogen may be prepared in the form of apharmaceutically acceptable salt, especially an acid addition salt.

For use in medicine, the salts of the compounds of formula I will benon-toxic pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds according to the inventionor of their non-toxic pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude addition salts which may, for example, be formed by mixing asolution of the compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulfuricacid, nitric acid, maleic acid, citric acid, tartaric acid, phosphoricacid, p-toluenesulfonic acid, benzenesulfonic acid. Preferredpharmaceutically salts of the compounds of the present invention arethose with the inorganic acids.

The salts may be formed by conventional means, such as by reacting thefree base form of the suitable compounds of formula I with one or moreequivalents of the appropriate acid in a solvent or medium in which thesalt is insoluble or in a solvent such as water which is removed undervacuum.

The present invention also includes within its scope N-oxide of thecompounds of formula I above. In general, such N-oxides may be formed onany available nitrogen atom. The N-oxides may be formed by conventionalmeans, such as reacting the compound of formula I with peroxides insuitable solvents. The present invention includes within its scopeprodrugs of the compounds of formula I above. In general, such prodrugswill be functional derivatives of the compounds of formula I which arereadily convertible in vivo into the required compound of formula I.Conventional procedures for the selection and preparation o suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985. A prodrug may be a pharmacologicallyinactive derivative of a biologically active substance (the “parentdrug” or “parent molecule”) that requires transformation within the bodyin order to release the active drug, and that has improved deliveryproperties over the parent drug molecule. The transformation in vivo maybe, for example, as the result of some metabolic process, such aschemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfateester, or reduction or oxidation of a susceptible functionality.

Examples of 5- or 6-membered monocyclic aromatic heterocycle rings arefuran, thiophene, pyrrole, imidazole, pyrazole, thiazole, isothiazole,oxazole, isoxazole, thiadiazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazine.

Examples of a bicyclic 9-11-membered aromatic heterocycles arebenzothiazole, benzoisothiazole, benzoxazole, benzoisoxazole,benzimidazole, benzotriazole, benzothiadiazole, benzooxadiazole,quinoline, isoquinoline, naphthylidine, quinoxaline, phthalazine,cinnoline, indole, indazole, imidazopyridine, benzothiophene,benzofuran, dihydrobenzofuran, benzazepine, benzodiazepine.

Examples of —C₁₋₄alkyl-monocyclic heteroaryl rings areC₁₋₄alkylsubstituted furan, thiophene, pyrrole, imidazole, pyrazole,thiazole, isothiazole, oxazole, isoxazole, thiadiazole, pyridine,pyrazine, pyrimidine, pyridazine,

Examples of —C₁₋₄alkyl-heterocycloalkyls are C₁₋₄alkylsubstitutedtetrahydrofuran, pyran.

In one embodiment each Y₁, Y₂ are CH and Y₃ is N.

In another embodiment each Y₁, Y₂ and Y₃ are CH.

In certain embodiments each Y₁, Y₂ and Y₃ are as above defined and Ar₁is:

i) phenyl substituted with one substituent R_(a); where R_(a) is halo,preferably —Cl or —F, or —C₁₋₄alkyl, preferably methyl;

ii) a thienyl ring optionally substituted with one substituents R_(a):where R_(a) is halo, preferably —Cl;

Ar₂ is:

i) phenyl substituted with 1 substituent R_(b); where R_(b) is—OC₀₋₄alkylCF₃₅ preferably OCF₃, or R_(b) is —CF₃;

R₁ is H or C₁₋₄ alkyl optionally substituted with halo, preferably H,methyl or ethyl;

R₂, R₃, R₄, and R₅ are each independently H, or —C₁₋₄alkyl, preferably Hor methyl;

R₆ is:

i) H;

ii) 1-pyrrolidinyl;

iii) phenyl optionally substituted with —CF₃ or —OCF₃;

iv) morpholin-yl.

Examples of Compounds of Formula I are

-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-fluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-(methyl(p-tolylsulfonyl)amino)-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]-methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]-methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]-phenyl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)-sulfonyl-ethyl-amino]prop-2-enamide;-   N-[[2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)-sulfonyl-methyl-amino]prop-2-enamide;-   (Z)-2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)-phenyl]-4-pyridyl]methyl]but-2-enamide;-   (Z)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamide;-   (Z)-2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)-phenyl]-phenyl]methyl]but-2-enamide;-   (Z)-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]but-2-enamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)-phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]cyclopropanecarboxamide;-   1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]-phenyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)-phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   2-[(3,4-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(3-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-(ethyl(2-thienylsulfonyl)amino)prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[1-oxido-2-[4-(trifluoromethyl)phenyl]pyridin-1-ium-4-yl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamide;-   2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide;-   N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide.

Compounds of Formula (I) are amides that can be prepared by standardprocedures, by the reaction of a compound of general formula i with thecorresponding amine ii in the presence of an acidic function activator,preferably diethyl cyanophosphonate DEPC as illustrated in the followingScheme 1.

According to a first preferred embodiment, the invention relates tocompounds of formula (IA)

wherein:

Ar₁ is:

i) phenyl substituted with 0, 1, 2 or 3 substituents R_(a); or

ii) a 5-6-membered monocyclic aromatic heterocycle ring optionallysubstituted with one or two substituents R_(a); where each R_(a) isindependently halo, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CN, —CF₃, —OCF₃, —NO₂,—C(O)C₁₋₄alkyl or —CO₂H;

Ar₂ is:

i) phenyl substituted with 0, 1, 2 or 3 substituents R_(b); where eachR_(b) is independently halo, —C₁₋₄alkyl, —C(O)NR_(c)R_(d), —OC₁₋₄alkyl,—OC₀₋₄alkylCF₃, —CN, —CF₃, —CF₂H, —NO₂, —NR_(c)R_(d), S(O)₀₋₂C₁₋₄alkyl,—C(O)C₁₋₄alkyl, S(O)(O)NH₂, —(CH₂)₀₋₂-morpholinyl, piperidin-1-yl,piperazinyl, said piperazinyl optionally substituted with a methyl, ortwo R_(b) substituents on adjacent carbon atoms taken together form—O(CH₂)₁₋₂O—;

ii) pyridyl substituted with 0, 1 or 2 substituents R_(e); where eachR_(e) is independently selected from halo, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CF₃, —NR_(e)R_(d) or 4-morpholinyl; or

iii) a bicyclic 9-11-membered aromatic heterocycle optionallysubstituted with 1 substituent R_(f); where R_(f) is —C₁₋₄alkyl;

R_(c) and R_(d) are each independently selected from H or —C₁₋₄alkyl;

R₁ is H, C₁₋₄alkyl-O—C₁₋₄alkyl, or C₁₋₄alkyl optionally substituted withhalo;

R₂ and R₃ and are each independently H, halo or —C₁₋₄alkyl;

each Y₁, Y₂ and Y₃ is independently CH or N;

R₆ 1 S

i) H, —C₁₋₄alkyl, —CF₃, —OR_(Z) or —NR_(h)R_(i);

where R_(h) is selected from

a) H, —C₀₋₄alkylCF₃, —C₁₋₄alkyl-N(CH₃)₂, saturated C₃₋₇cycloalkyl or—C₁₋₄alkyl-monocyclic heteroaryl ring;

b) —C₁₋₅alkyl optionally substituted with OH;

c) —C₁₋₄alkyl-heterocycloalkyl, said heterocycloalkyl being optionallysubstituted with —C₁₋₄alkyl: or

d) —C₀₋₄alkyl-phenyl, said phenyl optionally substituted with one or twoN moieties; where each R_(j) is independently halo, —OC₁₋₄alkyl,

R_(Z) is —C₁₋₄alkyl, —C₁₋₄alkylCF₃ or —C₁₋₄alkyl-heterocycloalkyl;

ii) 1-pyrrolidinyl optionally substituted with a moiety selected fromthe group consisting of —NR_(k)R_(i) and —C₁₋₄alkyl, said —C₁₋₄alkyloptionally substituted with —OH;

iii) 1-piperidinyl optionally substituted with —C₁₋₄alkyl, —C(O)NH₂,—CO₂C₁₋₄alkyl or —C₀₋₄alkyl-phenyl;

iv) piperazinyl optionally substituted with —C₁₋₅alkyl, —OC₁₋₄alkyl,—C₀₋₄alkylpyridyl, —C₀₋₄alkyl-1-methyl-piperidin-4-yl,—C₀₋₄alkylNR_(k)R_(i) or —C₀₋₄alkyl-phenyl, said phenyl optionallysubstituted with one or two R_(T) substituents; where each R_(T)substituent is selected from the group consisting of halo, —OCF₃,—C₁₋₄alkyl, —OC₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl and—C₀₋₄alkylNR_(k)R_(i), or two R_(T) substituents on adjacent carbonatoms taken together form —O(CH₂)₁₋₂O—;

v) phenyl optionally substituted with halo, —CF₃, —OCF₃;

vi) pyridyl;

vii) morpholin-yl;

R_(k) is H, —C₁₋₄alkyl or —C(O)₁₋₂C₁₋₄alkyl;

R_(i) is H or C₁₋₄alkyl.

In one embodiment, in the compounds of formula (IA) each Y₁, Y₂ are CHand Y₃ is N.

In another embodiment in the compounds of formula (IA) each Y₁, Y₂ andY₃ are CH In certain embodiments in the compounds of formula (IA) eachY₁, Y₂ and Y₃ are as above defined and

Ar₁ is:

i) phenyl substituted with one substituent R_(a); where R_(a) is halo,preferably —Cl or —F, or —C₁₋₄alkyl, preferably methyl;

ii) a thienyl ring optionally substituted with one substituents R_(a):where R_(a) is halo, preferably —Cl;

Ar₂ is:

i) phenyl substituted with 1 substituent R_(b); where R_(b) is—OC₀₋₄alkylCF₃₅ preferably OCF₃, or R_(b) is —CF₃;

R₁ is H or C₁₋₄ alkyl optionally substituted with halo, preferably H,methyl or ethyl;

R₂, R₃, R₄, and R₅ are each independently H, or —C₁₋₄alkyl, preferably Hor methyl;

R₆ 1 S:

i) H;

ii) 1-pyrrolidinyl;

iii) phenyl optionally substituted with —CF₃ or —OCF₃;

iv) morpholin-yl.

Examples of Compounds of Formula (IA) are

-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide-   2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-fluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-(methyl(p-tolylsulfonyl)amino)-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]-methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)-phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]-methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]-phenyl]methyl]prop-2-enamide-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide-   2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)-sulfonyl-ethyl-amino]prop-2-enamide;-   N-[[2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)-sulfonyl-methyl-amino]prop-2-enamide;-   (Z)-2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)-phenyl]-4-pyridyl]methyl]but-2-enamide;-   (Z)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamide;-   (Z)-2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)-phenyl]-phenyl]methyl]but-2-enamide;-   (Z)-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]but-2-enamide;-   2-[(3,4-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(3-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-(ethyl(2-thienylsulfonyl)amino)prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[1-oxido-2-[4-(trifluoromethyl)phenyl]pyridin-1-ium-4-yl]methyl]prop-2-enamide;-   2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamide;-   2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;-   N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide.

According to a second preferred embodiment, the invention relates tocompounds of formula (IB)

wherein:

Ar₁ is:

i) phenyl substituted with 0, 1, 2 or 3 substituents R_(a); or

ii) a 5- or 6-membered monocyclic aromatic heterocycle ring optionallysubstituted with one or two substituents R_(a); where each R_(a) isindependently halo, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CN, —CF₃, —OCF₃, —NO₂,—C(O)C₁₋₄alkyl or —CO₂H;

Ar₂ is:

i) phenyl substituted with 0, 1, 2 or 3 substituents R_(b); where eachR_(b) is independently halo, —C₁₋₄alkyl, —C(O)NR_(c)R_(d), —OC₁₋₄alkyl,—OC₀₋₄alkylCF₃, —CN, —CF₃, —OCF₂H, —NO₂, —NR_(c)R_(d),—S(O)₀₋₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl, S(O)(O)NH₂, —(CH₂)₀₋₂-morpholinyl,piperidin-1yl, piperazinyl, said piperazinyl optionally substituted witha methyl, or two R_(b) substituents on adjacent carbon atoms takentogether form —O(CH₂)₁₋₂O—;

ii) pyridyl substituted with 0, 1 or 2 substituents R_(e); where eachR_(e) is independently selected from halo, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CF₃, —NR_(e)R_(d) or 4-morpholinyl; or

iii) a bicyclic 9-11-membered aromatic heterocycle optionallysubstituted with 1 substituent R_(f); where R_(f) is —C₁₋₄alkyl;

R_(c) and R_(d) are each independently selected from H or —C₁₋₄alkyl;

R₁ is H, C₁₋₄alkyl-O—C₁₋₄alkyl, or C₁₋₄alkyl optionally substituted withhalo; R₂, R₃, R₄, and R₅ are each independently H, halo or —C₁₋₄alkyl;

each Y₁, Y₂ and Y₃ is independently CH or N;

R₆ is

i) H, —C₁₋₄alkyl, —CF₃, —OR_(Z) or —NR_(h)R_(i);

where R_(h) is selected from

a) H, —C₀₋₄alkylCF₃, —C₁₋₄alkyl-N(CH₃)₂, saturated C₃₋₇cycloalkyl or—C₁₋₄alkyl-monocyclic heteroaryl ring;

b) —C₁₋₅alkyl optionally substituted with OH;

c) —C₁₋₄alkyl-heterocycloalkyl, said heterocycloalkyl being optionallysubstituted with —C₁₋₄alkyl: or

d) —C₀₋₄alkyl-phenyl, said phenyl optionally substituted with one or twoN moieties; where each R_(j) is independently halo, —OC₁₋₄alkyl,

R_(Z) is —C₁₋₄alkyl, —C₁₋₄alkylCF₃ or —C₁₋₄alkyl-heterocycloalkyl;

ii) 1-pyrrolidinyl optionally substituted with a moiety selected fromthe group consisting of —NR_(k)R_(i) and —C₁₋₄alkyl, said —C₁₋₄alkyloptionally substituted with —OH;

iii) 1-piperidinyl optionally substituted with —C₁₋₄alkyl, —C(O)NH₂,—CO₂C₁₋₄alkyl or —C₀₋₄alkyl-phenyl;

iv) piperazinyl optionally substituted with —C₁₋₅alkyl, —OC₁₋₄alkyl,—C₀₋₄alkylpyridyl, —C₀₋₄alkyl-1-methyl-piperidin-4-yl,—C₀₋₄alkylNR_(k)R_(i) or —C₀₋₄alkyl-phenyl, said phenyl optionallysubstituted with one or two R_(T) substituents; where each R_(T)substituent is selected from the group consisting of halo, —OCF₃,—C₁₋₄alkyl, —OC₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O) C₁₋₄alkyl and—C₀₋₄alkylNR_(k)R_(i), or two R_(T) substituents on adjacent carbonatoms taken together form —O(CH₂)₁₋₂O—;

v) phenyl optionally substituted with halo, CF₃;

vi) pyridyl;

vii) morpholin-yl;

R_(k) is H, —C₁₋₄alkyl or —C(O)₁₋₂C₁₋₄alkyl;

R_(i) is H or C₁₋₄alkyl

In one embodiment, in the compounds of formula (IB) each Y₁, Y₂ are CHand Y₃ is N.

In another embodiment in the compounds of formula (IB) each Y₁, Y₂ andY₃ are CH.

In another embodiments, in the compounds of formula (IB) each Y₁, Y₂ andY₃ are as above defined and

Ar₁ is:

i) phenyl substituted with one substituent R_(a); where R_(a) is halo,preferably —Cl or —F, or —C₁₋₄alkyl, preferably methyl;

ii) a thienyl ring optionally substituted with one substituents R_(a):where R_(a) is halo, preferably —Cl; Ar₂ is:

i) phenyl substituted with 1 substituent R_(b); where R_(b) is—OC₀₋₄alkylCF₃₅ preferably OCF₃, or R_(b) is —CF₃;

R₁ is H or C₁₋₄ alkyl optionally substituted with halo, preferably H,methyl or ethyl; R₂, R₃, R₄, and R₅ are each independently H, or—C₁₋₄alkyl, preferably H or methyl;

R₆ is:

i) H;

ii) 1-pyrrolidinyl;

iii) phenyl optionally substituted with —CF₃ or —OCF₃;

iv) morpholin-yl.

Examples of Compounds of Formula (IB) are

-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)-phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]-methyl]cyclopropanecarboxamide;-   1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]-phenyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]-phenyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)-phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;-   N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;-   1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide.

Compounds of formula (IA) and (IB) are amides that can be prepared bystandard procedures, by the reaction of a compound of general formula(IIa) or (IIb) with the corresponding amine (III) in the presence of anacidic function activator such as, for example, DEPC, as illustrated inthe following Scheme 2.

The compounds of formula (IIa) or (IIb) and the compounds of formula(III) are known compounds that can be prepared according to wellestablished procedures, as it will be illustrated in the Examples and inSchemes 3-7 accompanying the Examples.

Compositions of the Invention

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention that may beformulated together with one or more non-toxic pharmaceuticallyacceptable carriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), buccally or as an oral or nasal spray.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as, but not limited to, lactose,glucose and sucrose; starches such as, but not limited to, corn starchand potato starch; cellulose and its derivatives such as, but notlimited to, sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as, but not limited to, cocoa butter and suppository waxes; oilssuch as, but not limited to, peanut oil, cottonseed oil, safflower oil,sesame oil, olive oil, corn oil and soybean oil; glycols; such apropylene glycol; esters such as, but not limited to, ethyl oleate andethyl laurate; agar; buffering agents such as, but not limited to,magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol, and phosphatebuffer solutions, as well as other non-toxic compatible lubricants suchas, but not limited to, sodium lauryl sulfate and magnesium stearate, aswell as coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of theformulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnon-aqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents that delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution, which in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly (orthoesters) andpoly (anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions that are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragées, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient (s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals, which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospho lipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N. Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants that may berequired. Ophthalmic formulations, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

In the treatment of painful conditions such as those listed below, asuitable indicated dosage level is about 0.1 mg to 2000 mg/day,preferably from about 5 mg to 1000 mg per day. The compounds may beadministered on a regimen of 1 to 4 times a day.

It will be appreciated that the amount of a compound of formula Irequired for use in any treatment will vary not only with the particularcompounds or compositions selected but also with the route ofadministration, the nature of the condition being treated, and the ageand condition of the patient.

The agents of invention are useful TRPA1 receptor antagonists for thetreatment of pain of various genesis or etiology and asanti-inflammatory agents for the treatment of inflammatory reactions,diseases or conditions. They are useful for the treatment ofinflammatory pain, for the treatment of hyperalgesia, and in particularfor the treatment of severe chronic pain. They are, for example, usefulfor the treatment of neuropathic pain conditions such as diabeticneuropathy, chemotherapy-induced neuropathy and post-herpetic neuralgia;“non-painful” neuropathies, complex regional pain syndromes, painassociated with carcinoma, often referred to as cancer pain, centralnervous system pain, such as pain due to spinal cord or brain stemdamage, low back pain, sciatica and ankylosing spondylitis, inflammationconsequential to trauma, e.g. associated with burns or subsequent tosurgical intervention, e.g. as post-operative analgesics, as well as forthe treatment of inflammatory pain of diverse genesis, e.g. for thetreatment of osteoarthritis and rheumatoid arthritis.

Other forms of pain associated with the activity of TRPA1 are headache,dental pain, pelvic pain, migraine, mastalgia and visceral pain.

The disorders in which TRPA1 is involved are not limited to pain. Suchdiseases include: nerve-related diseases, e.g. neuropathies, nerveinjury and stroke; irritable bowel syndrome; gastrointestinal disorders,e.g. gastro-oesophageal reflux disease, Crohn's disease; respiratorydiseases, e.g. asthma, chronic obstructive pulmonary disease, cough;

urinary incontinence; urinary bladder hypersensitiveness; skin diseases,e.g. psoriasis, dermatitis; cardiac diseases e.g. myocardial ischemia;hair growth related disorders e.g. hirsutism, alopecia; rhinitis;pancreatitis; vulvodynia; psychiatric disorders, e.g. anxiety or fear;obesity.

The compounds of the present invention have potent analgesic effect andpotential anti-inflammatory activity and their pharmaceuticallyformulations are thought to alleviate or to treat in particularneuropathic pain conditions such as diabetic neuropathy andpost-herpetic neuralgia, urinary incontinence, COPD and cough.

The invention will be now illustrated by means of the followingexamples.

EXAMPLES

All commercially available compounds were purchased from Vendors andwere used without further purification. Reaction courses were monitoredby thin-layer chromatography on silica gel (precoated F₂₅₄ Merckplates), the spots were examined with UV light and visualized withaqueous KMnO₄. Flash chromatography was performed using Merck silica gel(230-240 mesh). ¹H-NMR spectra were recorded on Varian 400 MHzspectrometer or Varian 200 MHz using TMS as internal standard. Massspectra were obtained with a Waters-Micromass ZMD spectrometer.

Abbrev.: TEA (triethylamine), DMF (dimethylformamide), DEPC(diethylcyanophosphonate), TetrakisPd (tetrakistriphenylphosphinePalladium(O)), DME (Dimethoxyethane), XPhos(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl).

Example 12-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl(2S)-2-[(4-fluorophenyl)sulfonylamino]-3-hydroxy-propanoate 2A

A suspension of L-serine-methyl ester hydrochloride 1 (5 g, 32.13 mmol)in CH₂Cl₂ (100 mL) was added with TEA (1.1 mol eq, 4.9 mL) and themixture stirred at r.t. for 10 minutes. Then 4-fluorobenzensulfonylchloride (1 mol eq, 6.26 g) and additional TEA (1.1 mol eq) were addedand the resulting solution heated at 50° C. for 6 h. The solvent wasremoved under reduced pressure, water was added to the residue (100 mL)and the aqueous phase finally extracted with EtOAc (3×40 mL). Thecombined organic phases were dried over Na₂SO₄ and evaporated underreduced pressure. The residue was recrystallized from ethyl ether toafford 2A as white solid (7.10 g, 80% yield). ¹HNMR (DMSO, 200 MHz) δ3.48 (s, 3H), 3.53 (m, 2H), 3.86 (t, 1H), 5.07 (t, 1H), 7.41 (m, 2H),7.83 (m, 2H), 8.33 (bs, 1H).

Synthesis of methyl(2S)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-3-hydroxy-propanoate 3B

A solution of 2A (1 g, 3.6 mmol) in DMF (15 mL) was added with an. K₂CO₃(1.4 mol eq, 0.7 g) and, after few minutes, 2-iodoethane (1.2 mol eq,0.45 ml) was added and the mixture heated at 50° C. for 5 h. The solventwas removed under reduced pressure, water was added to the residue (80mL) and the aqueous phase extracted with EtOAc (3×30 mL). The combinedorganic phases were dried using Na₂SO₄ and evaporated under reducedpressure to obtain 3B as a pale yellow oil (1.1 g, quantitative yield).¹HNMR (DMSO, 200 MHz) δ 1.13 (t, 3H, J=8), 3.29 (q, 2H), 3.41 (s, 3H),3.79 (m, 2H), 4.53 (t, 1H), 5.14 (t, 1H), 7.41 (t, 2H, J=10), 7.86 (m,2H).

Synthesis of 2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enoic acid4B

A solution of 3B (1.1 g, 3.6 mmol) in dioxane (25 mL) was added with 20%NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 4 h. Theorganic solvent was removed under reduced pressure and the aqueous phaseacidified with 10% HCl and extracted with CH₂Cl₂ (3×30 mL). The combinedorganic phases were dried using Na₂SO₄, evaporated under reducedpressure and then the resulting residue purified by flash chromatography(100% EtOAc) to obtain 4B as white solid (0.7 g, 66% yield). ¹HNMR(DMSO, 200 MHz) δ 1.12 (t, 3H), 3.29 (q, 2H), 5.69 (s, 1H), 6.32 (s,1H), 7.39 (m, 2H), 7.89 (m, 2H), 12.9 (bs, 1H).

Synthesis of 2-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile 20A

2-Chloropyridine-4-carbonitrile 19 (2.96 g, 21.35 mmol) was dissolved in100 ml of dimethoxyethane. The solution was added with 70 ml of water,sodium bicarbonate (3 equiv., 5.38 g),[4-(trifluoromethyl)phenyl]boronic acid (1.2 equiv., 4.87 g) and themixture was then stirred at rt for 5′. The mixture was degassed andplaced under argon. A catalytic amount of tetrakispalladium was addedand the mixture heated at 100° C. overnight. The solvents wereevaporated off and the resulting residue dissolved with ethyl acetateand then washed with water and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The crude was crystallizedfrom ethyl acetate and petroleum ether to give a beige solid. (2.5 g,47% yield).

Synthesis of [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A

The nitrile 20A (3 g, 12 mmol) dissolved in 50 ml of diethyl ether wasadded dropwise to a mixture of LiAlH₄ (912 mg, 2 equiv.) in diethylether (80 mL) and stirred at 0° C. Then, the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was destroyed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was dried over Na₂SO₄ and evaporated to dryness to obtain2.5 g of the amine as a yellow oil. The amine was used for the followingstep without purification.

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 1

Acid 4B (273.28 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv.,277.5 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded100 mg of a white solid. Yield=19% ¹HNMR (DMSO, 400 MHz) δ 1.09 (3H, t,J=7.2 Hz), 3.39 (2H, q, J=6.8 Hz), 4.48 (2H, d, J=6 Hz), 5.15 (1H, s),6.14 (1H, s), 7.36 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.47 (2H, t, J=8.8Hz), 7.84 (4H, m), 8.01 (1H, s), 8.30 (2H, d, J=8 Hz), 8.64 (1H, dd,J=5.2 Hz, J′=0.8 Hz), 8.89 (1H, bt) [M⁺¹] 508.7 (C₂₄H₂₁F₄N₃O₃S requires507.50).

Example 22-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl(2S)-2-[(4-fluorophenyl)sulfonyl-methyl-amino]-3-hydroxy-propanoate 3A

A solution of 2A (2 g, 7.2 mmol) in DMF (20 mL) was added with an. K₂CO₃(1.5 mol eq, 1.49 g) and, after few minutes, iodomethane (1.2 mol eq,0.8 ml) was added and the mixture heated at 50° C. for 12 h. The solventwas removed under reduced pressure, water was added to the residue (100mL) and the aqueous phase extracted with EtOAc (3×40 mL). The combinedorganic phases were dried over Na₂SO₄ and evaporated under reducedpressure to obtain 3A as a pale yellow oil (2.3 g, quantitative yield).¹HNMR (DMSO, 200 MHz) δ 2.82 (s, 3H), 3.50 (s, 3H), 3.69 (m, 3H), 4.60(t, 1H, J=6), 5.12 (t, 1H, J=6.1), 7.44 (m, 2H), 7.83 (m, 2H).

Synthesis of 2-[(4-fluorophenyl)sulfonyl-methyl-amino]prop-2-enoic acid4A

A solution of 3A (2.3 g, 7.2 mmol) in dioxane (35 mL) was added with 20%NaOH aq. solution (20 mL) and the mixture was heated at 50° C. for 2 h.The organic solvent was removed under reduced pressure and the aqueousphase acidified with 10% HCl. The solid formed was collected byfiltration, washed with water (2×20 mL) and dried to obtain 4A as whitesolid (1.05 g, 51% yield). ¹HNMR (DMSO, 200 MHz) δ 2.92 (s, 3H), 5.57(s, 1H), 6.09 (s, 1H), 7.50 (m, 2H), 7.85 (m, 2H), 13.01 (bs, 1H).

Synthesis of 2-[4-(trifluoromethoxy)phenyl]pyridine-4-carbonitrile 20B

A solution of 19 (2.5 g, 18 mmol) in DME (90 mL) was added4-trifluoromethoxy phenyl boronic acid (1.1 mol eq, 4.46 g) and NaHCO₃(3 mol eq, 4.66 g) suspended in water (50 mL). The mixture was degassedunder vacuum, then Tetrakispalladium was added (catalytic amount) andthe reaction stirred at 100° C. under inert atmosphere for 12 h. Thesolvent was removed under reduced pressure and water was added to theresidue (100 mL). The aqueous phase was extracted with EtOAc (3×50 mL)and the combined organic layer was washed with brine (100 mL) and driedover Na₂SO₄. The solvent was evaporated under vacuum to obtain 20B as apale yellow crystals (96% Yield, 4.6 g, 17.4 mmol). ¹HNMR (DMSO, 200MHz) δ 7.5 (dd, 2H, J=2), 7.84 (dd, 1H, J=1.8), 8.31 (d, 2H, J=9.8),8.54 (d, 1H, J=2), 8.93 (dd, 1H, J=1.9).

Synthesis of [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B

A solution of nitrile 20B (3 g, 11.3 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.9 g, 2 mol eq) indiethyl ether (35 mL) and stirred at 0° C. After the addition wascompleted, the mixture was stirred at room temperature overnight. Theexcess of LiAlH₄ was destroyed at 0° C. by addition of small amount ofwater (30 mL), the solid formed was filtered off and the organicfiltrate separated, washed with brine (50 mL) and dried over Na₂SO₄. Theorganic phase was evaporated under reduced pressure to obtain 21B as ayellow oil (3.1 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 308 (s,2H), 3.8 (bs, 2H), 7.33 (dd, 1H, J=1.8), 7.47 (dd, 2H, J=2), 7.96 (s,1H), 8.20 (dd, 2H, J=1.8), 8.57 (dd, 1H, J=1.2).

Preparation of2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 2

A solution of acid 4A (0.26 g, 1 mmol) in THF (25 mL) was added withDEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.27 g, 1.1mol eq) and a catalytic amount of TEA were added. The reaction mixturewas then stirred at room temperature overnight. The solvent was removedunder reduced pressure, the residue was suspended in EtOAc (30 mL) andwashed with water (50 mL) and brine. The separated organic phase, afterdrying over Na₂SO₄, was evaporated under reduced pressure and theresidue was purified by flash chromatography (8:2 EtOAc:Petroleum ether)to afford a pale yellow solid (0.1 g) after crystallization from amixture of diethyl ether/petroleum ether. Yield=23%, ¹HNMR (DMSO, 200MHz) δ 2.95 (3H, s), 4.49 (d, 2H, J=6 Hz), 5.10 (s, 1H), 5.88 (s, 1H),7.35 (dd, 1H), 7.47 (m, 4H), 7.48 (m, 2H), 7.96 (s, 1H), 8.21 (dd, 2H),8.61 (d, 1H, J=4 Hz), 8.94 (t, 1H); [M⁺¹] 509.47 (C₂₃H₁₉F₄N₃O₄S requires509.10).

Example 32-[(4-fluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(4-fluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 3

A solution of acid 4B (0.25 g, 1 mmol) in THF (20 mL) was added withDEPC (0.17 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.27 g, 1.1mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, the residue was suspended in EtOAc (30mL) and washed with water (50 mL) and brine. The separated organicphase, after drying over Na₂SO₄, was evaporated under reduced pressureand the residue purified by flash chromatography (7:3 EtOAc:Petroleumether) to afford a pale orange solid (0.12 g) after crystallization froma mixture of diethyl ether/petroleum ether.

Pale yellow solid. Yield=30%, ¹HNMR (DMSO, 200 MHz) δ 1.08 (t, 3H, J=6.8Hz), 3.40 (q, 2H), 4.48 (d, 2H, J=6), 5.15 (s, 1H), 6.14 (s, 1H), 7.29(d, 1H), 7.43 (m, 4H), 7.86-7.88 (m, 3H), 8.21 (d, 2H), 8.58 (d, 1H),8.85 (t, 1H); [M⁺¹] 523.50 (C₂₄H₂₁F₄N₃O₄S requires 523.14).

Example 42-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl(2S)-2-[(4-chlorophenyl)sulfonylamino]-3-hydroxy-propanoate 2C

A suspension of L-serine-methyl ester hydrochloride (5 g, 32.13 mmol) inCH₂Cl₂ (100 mL) was added with TEA (1.1 mol eq, 4.9 mL) and the mixturewas stirred at r.t. for 10 minutes. Then 4-chlorobenzensulfonyl chloride(1 mol eq, 6.81 g) and additional TEA (1.1 mol eq) were added and thesolution hated at 50° C. for 5 h. The solvent was removed under reducedpressure, water was added to the residue (100 mL) and the aqueous phaseextracted with EtOAc (3×40 mL). The combined organic phases were driedover Na₂SO₄ and evaporated to reduced pressure. The residue wasrecrystallized from ethyl ether to afford 2C as white solid (8.6 g, 91%yield). ¹HNMR (DMSO, 200 MHz) δ 3.51 (s, 3H), 3.60 (m, 2H), 3.91 (t,1H), 5.17 (t, 1H), 7.50 (d, 2H, J=8), 7.89 (d, 2H, J=7.8)), 8.35 (bs,1H).

Synthesis of methyl(2S)-2-[(4-chlorophenyl)sulfonyl-methyl-amino]-3-hydroxy-propanoate 3C

A solution of 2C (8.5 g, 28 mmol) in DMF (30 mL) was added with an.K₂CO₃ (1.5 mol eq, 5.99 g) and, after few minutes, iodomethane (1.2 moleq, 3.21 mL) was added and the mixture heated at 50° C. for 12 h. Thesolvent was removed under reduced pressure, water was added to theresidue (150 mL) and the aqueous phase extracted with EtOAc (3×60 mL).The combined organic phases were dried over Na₂SO₄ and evaporated underreduced pressure to afford 3C as a pale yellow oil (8.6 g, 97% yield).¹HNMR (DMSO, 200 MHz) δ 2.88 (s, 3H), 3.52 (s, 3H), 3.66 (m, 2H), 4.02(q, 1H, J=6), 4.602 (t, 1H, J=6.1), 5.11 (t, 1H), 7.64 (d, 2H), 7.76 (d,2H).

Synthesis of 2-[(4-chlorophenyl)sulfonyl-methyl-amino]prop-2-enoic acid4C

A solution of 3C (8.5 g, 27.6 mmol) in dioxane (20 mL) was added with20% NaOH aq. solution (30 mL) and the mixture heated at 80° C. for 5 h.The organic solvent was removed under reduced pressure and the aqueousphase acidified with 10% HCl and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic phases were dried over Na₂SO₄ and evaporated underreduced pressure to afford 4C as a pale yellow deliquescent solid (4.3g, 62% yield). ¹HNMR (DMSO, 200 MHz) δ 2.91 (s, 3H), 5.58 (s, 1H), 6.09(s, 1H), 7.72-7.60 (m, 4H), 13.05 (bs, 1H).

Preparation of2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 4

A solution of acid 4C (0.50 g, 1.8 mmol) in THF (30 mL) was added withDEPC (0.35 mL, 1.3 mol eq) and the mixture stirred at room temperatureseveral minutes. Then[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.53 g, 1.1mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, the residue was suspended in EtOAc andwashed with water and brine. The separated organic phase was dried overan. Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford apale yellow viscous oil (0.17 g). Yield=18%, ¹HNMR (DMSO, 200 MHz) δ2.98 (s, 3H), 4.22 (d, 2H), 5.08 (s, 1H), 5.85 (s, 1H), 7.4 (m, 3H),7.65 (dd, 4H, J=8), 7.95 (s, 1H), 8.2 (d, 2H), 8.58 (d, 1H), 8.95 (t,1H); [M⁺¹] 525.93 (C₂₃H₁₉ClF₃N₃O₄S requires 525.07).

Example 52-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of ethyl(2S)-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-3-hydroxy-propanoate 3D

Compound 2C (1.65 g, 5.6 mmol) dissolved in DMF (15 ml) was added withK₂CO₃ (1.1 equiv., 854 mg) and ethyl iodide (1.1 equiv., 0.63 ml) andthe reaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 1.6 g of a semisolid.Yield=88%. ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.2 Hz), 3.32 (3H, s),3.34 (2H, m), 3.75 (2H, m), 4.42 (1H, t), 5.08 (1H, bs), 7.62 (2H, m),7.76 (2H, m)

Synthesis of 2-[(4-chlorophenyl)sulfonyl-ethyl-amino]prop-2-enoic acid4D

Compound 3D (1.4 g, 4.45 mmol) dissolved in THF (20 ml) and water (5 ml)was added with LiOH.H₂O (3 equiv., 560 mg) and the reaction was stirredat rt 3 hours. The reaction was concentrated under vacuum. Water wasadded and 10% HCl till precipitation of the acid. The acid was extractedwith ethyl acetate and the organic phase was washed with Brine, driedover sodium sulfate and concentrated under vacuum to give 1.3 g of awhite solid. Yield=95%. ¹HNMR (DMSO, 200 MHz) δ 1.17 (3H, t, J=7.8 Hz),3.32 (2H, m), 3.76 (2H, m), 4.42 (1H, t), 5.08 (1H, bs), 7.61 (2H, m),7.82 (2H, m), 12.85 (1H, bs). The intermediate acid (1.23 g, 4 mmol)dissolved in pyridine (10 ml) was added dropwise with acetyl chloride(1.4 equiv., 0.45 ml) at 0° C. and the reaction was then stirred at rtfor 5 hours. The reaction was quenched by addition of 10% HCl and thenextracted with ethyl acetate. The organic phase was washed 2 times withwater, with brine, dried over sodium sulfate and concentrated undervacuum. The crude product was crystallized from diethyl ether andpetroleum ether to give 500 mg of a beige solid. Yield=43%. ¹HNMR (DMSO,200 MHz) δ 1.00 (3H, t, J=7.2 Hz), 3.40 (2H, m), 5.72 (1H,$), 6.33 (1H,s), 7.72 (4H, m), 13.00 (1H, bs)

Preparation of2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 5

Acid 4D (221.45 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv.,295 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in EtOAc (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded100 mg of a white solid. Yield=18.5% ¹HNMR (DMSO, 400 MHz) δ 1.08 (3H,t), 3.40 (2H, q), 4.42 (2H, d), 5.20 (1H, s), 6.08 (1H, s), 7.23 (1H,d), 7.45 (2H, d), 7.72 (4H, dd), 7.85 (1H, s), 8.20 (2H, d), 8.60 (1H,d), 8.74 (1H, bt) [M⁺¹] 540.1 (C₂₄H₂₁ClF₃N₃O₄S requires 539.95).

Example 62-(methyl(p-tolylsulfonyl)amino)-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl (2S)-3-hydroxy-2-(p-tolylsulfonylamino)propanoate 2E

A suspension of L-serine-methyl ester hydrochloride 1 (5 g, 32.13 mmol)in CH₂Cl₂ (150 mL) was added with TEA (1.1 mol eq, 4.92 mL) and themixture was stirred at r.t. for 10 minutes. Then p-tolylbenzensulfonylchloride (1 mol eq, 6.14 g) and additional TEA (1.1 mol eq) were addedand the solution was heated at 50° C. for 5 h. The solvent was removedunder reduced pressure, water was added to the residue (150 mL) and theaqueous phase extracted with EtOAc (3×50 mL). The combined organicphases were dried over Na₂SO₄ and evaporated under reduced pressure toafford 2E as white solid (8.10 g, 90% yield).

¹HNMR (DMSO, 200 MHz) δ 2.37 (s, 3H), 3.44 (s, 3H), 3.50 (m, 2H), 3.81(t, 1H), 5.04 (t, 1H, J=5.8), 7.38 (d, 2H, J=8), 7.66 (d, 2H, J=7.9),8.15 (bd, 1H).

Synthesis of methyl(2S)-3-hydroxy-2-(methyl(p-tolylsulfonyl)amino)propanoate 3E

A solution of 2E (2 g, 7.35 mmol) in DMF (15 mL) was added with an.K₂CO₃ (1.5 mol eq, 1.52 g) and, after few minutes, iodomethane (1.2 moleq, 0.81 ml) was added and the mixture was heated at 50° C. overnight.The solvent was removed under reduced pressure, water was added to theresidue (120 mL) and the aqueous phase was extracted with EtOAc (3×50mL). The combined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 3E as a pale yellow oil (2.1 g,quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 2.38 (s, 3H), 2.87 (s, 3H),3.64 (s, 3H), 3.70 (t, 2H), 4.58 (t, 1H), 5.11 (t, 1H), 7.40 (d, 2H,J=8), 7.61 (d, 2H, J=8).

Synthesis of 2-(methyl(p-tolylsulfonyl)amino)prop-2-enoic acid 4E

A solution of 3E (1.4 g, 4.87 mmol) in dioxane (30 mL) was added with20% NaOH aq. solution (30 mL) and the mixture was heated at 60° C.overnight. The organic solvent was removed under reduced pressure andthe aqueous phase was acidified with 10% HCl and extracted with CH₂Cl₂(3×50 mL). The combined organic phases were dried over Na₂SO₄ andevaporated under reduced pressure to afford 4E as a pale yellow solid(0.8 g, 65% yield). ¹HNMR (DMSO, 200 MHz) δ 2.81 (s, 3H), 2.88 (s, 3H),5.46 (s, 1H), 6.02 (s, 2H), 7.41 (d, 2H, J=7.8), 7.66 (d, 2H, H=8),13.01 (bs, 1H).

Preparation of2-(methyl(p-tolylsulfonyl)amino)-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 6

A solution of acid 4E (0.57 g, 2.2 mmol) in THF (30 mL) was added withDEPC (0.43 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.66 g, 1.1mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, the residue was suspended in EtOAc andwashed with water and brine. The separated organic phase was evaporatedunder reduced pressure and the residue was purified by flashchromatography (7:3 EtOAc:Petroleum ether) to afford a pale yellow solid(0.27 g) after crystallization from a mixture of diethyl ether/petroleumether. Yield=25%, ¹HNMR (DMSO, 200 MHz) δ 2.48 (s, 3H), 2.86 (s, 3H),4.49 (d, 2H, J=6), 5.00 (s, 1H), 5.85 (s, 1H), 7.35 (d, 1H), 7.42 (m,4H), 7.71 (d, 2H, J=8.2), 7.97 (s, 1H), 8.21 (dd, 2H, J=2.2), 8.61 (d,1H, J=4), 8.90 (t, 1H); [M⁺¹] 505.51 (C₂₄H₂₂F₃N₃O₄S requires 505.12).

Example 72-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl(2S)-2-[(5-chloro-2-thienyl)sulfonylamino]-3-hydroxy-propanoate 5

L-Serine methyl ester hydrochloride (5 g, 32.13 mmol) dissolved inmethylene chloride (200 ml) was added with TEA (2 equiv., 8.95 ml) andin one portion 5-chlorothiophene-2-sulfonyl chloride (1.0 equiv., 6.97g). The reaction was refluxed for 4 hours. The solvent was evaporatedand the crude was dissolved in AcOEt (100 ml) and washed with water(1×80 ml) and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bycrystallization from diethyl ether and petroleum ether afforded 10 g ofthe white product. Yield=93% ¹HNMR (DMSO, 200 MHz) δ 2.81 (2H, q, J=7.2Hz), 3.52 (3H, s), 3.92 (1H, t), 5.06 (1H, bs), 7.24 (1H, dd, J=4.2 Hz),7.45 (1H, dd, J=4 Hz), 8.92 (1H, bs)

Synthesis of methyl(2S)-2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-3-hydroxy-propanoate 6

Compound 5 (10 g, 30 mmol) dissolved in DMF (100 ml) was added withK₂CO₃ (1.1 equiv., 4.56 g) and ethyl iodide (1.1 equiv., 3.16 ml) andthe reaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 10 g of a semisolid.Yield=93%. ¹HNMR (DMSO, 200 MHz) δ 1.17 (3H, t, J=7 Hz), 3.40 (2H, q),3.54 (3H, s), 3.80 (2H, t, J=5.8 Hz), 4.50 (1H, t), 5.00 (1H, bt), 7.28(1H, dd, J=4 Hz, J′=1 Hz), 7.57 (1H, dd, J=4.2 Hz, J′=1 Hz).

Synthesis of 2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]prop-2-enoicacid 7

Compound 6 (10 g, 28 mmol) dissolved in THF (100 ml) and water (50 ml)was added with LiOH.H₂O (3 equiv., 3.52 g) and the reaction was stirredat rt 3 hours. The reaction was concentrated under vacuum. Water wasadded and 10% HCl till precipitation of the acid. The acid was extractedwith ethyl acetate and the organic phase was washed with Brine, driedover sodium sulfate and concentrated under vacuum to give 8 g of a whitesolid. Yield=81.5%. ¹HNMR (DMSO, 200 MHz) δ 1.17 (3H, t, J=5.6 Hz), 3.35(2H, q), 4.04 (2H, q, J=7 Hz), 4.39 (1H, t), 5.96 (1H, bs), 7.26 (1H,dd, J=4 Hz, J′=0.6 Hz), 7.55 (1H, dd, J=3.8 Hz, J′=0.4 Hz), 12.98 (1H,bs). The intermediate acid (2.45 g, 7 mmol) dissolved in pyridine (10ml) was added dropwise with acetyl chloride (1.4 equiv., 0.8 ml) at 0°C. and the reaction was then stirred at rt for 5 hours The reaction wasquenched by addition of 10% HCl and then extracted with ethyl acetate.The organic phase was washed 2 times with water, with brine, dried oversodium sulfate and concentrated under vacuum. The crude product wascrystallized from diethyl ether and petroleum ether to give 1 g of abeige solid. Yield=43%. ¹HNMR (DMSO, 200 MHz) δ 1.04 (3H, t, J=7.4 Hz),3.44 (2H, q), 5.82 (1H, s), 6.39 (1H, s), 7.31 (1H, d, J=4.2 Hz), 7.55(1H, d, J=4 Hz), 13.05 (1H, bs) Preparation of2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 7

Acid 7 (665 mg, 2 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.3 ml) and[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv.,590 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded200 mg of a pale yellow solid. Yield=18.3% ¹HNMR (DMSO, 200 MHz) δ 1.12(3H, t, J=7 Hz), 3.47 (2H, q, J=7.2 Hz), 4.48 (2H, d, J=6 Hz), 5.41 (1H,s), 6.25 (1H, s), 7.28 (2H, m), 7.48 (2H, d, J=7.8 Hz), 7.60 (1H, d,J=4.2 Hz), 7.90 (1H, bs), 8.19 (2H, dd, J=6.8 Hz), 8.61 (1H, d, J=5 Hz),8.89 (1H, bt) [M⁺¹] 546.1 (C₂₂H₁₉ClF₃N₃O₄S₂ requires 545.98).

Example 82-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamide

Synthesis of [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine 23A

A suspension of 3-bromobenzylamine hydrochloride 22 (1 g, 4.49 mmol) inDME (50 mL) was added with 4-trifluoromethyl phenyl boronic acid (1.2mol eq, 1.0 g) and NaHCO₃ (3 mol eq, 1.13 g) suspended in water (30 mL).The mixture was degassed under vacuum, then Tetrakispalladium was added(catalytic amount) and the reaction was stirred at 100° C. under inertatmosphere for 12 h. The solvent was removed under reduced pressure andwater was added to the residue (80 mL). The aqueous phase was extractedwith EtOAc (3×40 mL) and the combined organic layer was washed withbrine (50 mL) and dried over Na₂SO₄. The solvent was evaporated undervacuum to afford 23A as a pale brown oil (1.5 g, quantitative yield).

¹HNMR (DMSO, 400 MHz) δ 1.86 (bs, 2H), 3.79 (s, 2H), 7.39 (d, 1H), 7.44(t, 1H), 7.56 (d, 1H), 7.71 (s, 1H), 7.82 (d, 2H), 7.90 (d, 2H).

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamideExample 8

A solution of acid 4B (0.30 g, 1.1 mmol) in THF (20 mL) was added withDEPC (0.22 mL, 1.3 mol eq) and the mixture stirred at room temperaturefor 10 minutes. Then [3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine23A (0.303 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (45 mL) and washed with water (50 mL) and brine. The separatedorganic phase was dried over an. Na₂SO₄ and evaporated under reducedpressure. The residue was purified by flash chromatography (3:7EtOAc:Petroleum ether) to afford a white solid (0.11 g). Yield=22%,¹HNMR (DMSO, 200 MHz) δ. 1.089 (t, 3H), 3.38 (m, 2H), 4.46 (d, 2H,J=4.2), 5.16 (s, 1H), 6.09 (s, 1H), 7.35 (d, 1H), 7.43 (m, 3H), 7.60 (d,1H), 7.69 (s, 1H), 7.78 (d, 2H), 7.88 (m, 4H), 8.79 (bs, 1H). [M⁺¹]506.51 (C₂₅H₂₂F₄N₂O₃S requires 506.12).

Example 92-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamide

Preparation of2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamideExample 9

Acid 4C (827 mg, 3 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.5 ml) and [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine23A (1.1 equiv., 835 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:petroleumether) afforded 200 mg of a beige solid. Yield=13% ¹HNMR (DMSO, 200 MHz)δ 2.93 (3H, s), 4.44 (2H, d, J=5.8 Hz), 5.13 (1H, s), 5.85 (1H, s), 7.76(12H, m), 8.82 (1H, bt) [M⁺¹] 509.1 (C₂₄H₂₀ClF₃N₂O₃S requires 508.94).

Example 102-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamide

Preparation of2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamideExample 10

Acid 4D (869 mg, 3 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.5 ml) and [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine23A (1.1 equiv., 835 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:petroleumether) afforded 200 mg of a beige solid. Yield=13% ¹HNMR (DMSO, 200 MHz)δ 1.06 (3H, t, J=7 Hz), 3.39 (2H, q, J=7 Hz), 4.44 (2H, d, J=6 Hz), 5.20(1H, s), 6.10 (1H, s), 7.40 (1H, d), 7.46 (1H, t, J=7.6 Hz), 7.76 (10H,m), 8.79 (1H, bt) [M⁺¹] 523.1 (C₂₅H₂₂ClF₃N₂O₃S requires 522.97).

Example 112-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamide

Synthesis of [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine 23B

A suspension of 3-bromobenzylamine hydrochloride 22 (1 g, 4.49 mmol) inDME (50 mL) was added with 4-trifluoromethoxy phenyl boronic acid (1.2mol eq, 1.11 g) and NaHCO₃ (3 mol eq, 1.13 g) suspended in water (30mL). The mixture was degassed under vacuum, then Tetrakispalladium wasadded (catalytic amount) and the reaction was stirred at 100° C. underinert atmosphere for 12 h. The solvent was removed under reducedpressure and water was added to the residue (80 mL). The aqueous phasewas extracted with EtOAc (3×40 mL) and the combined organic layer waswashed with brine (50 mL) and dried over Na₂SO₄. The solvent wasevaporated under vacuum to afford 23B as a pale brown oil (1.5 g,quantitative yield).

¹HNMR (DMSO, 200 MHz) δ 3.80 (bs, 2H), 3.77 (s, 2H), 7.42 (m, 2H), 7.52(d, 1H), 7.68 (s, 1H), 7.79 (d, 2H), 7.89 (d, 2H)

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamideExample 11

A solution of acid 4B (0.35 g, 1.28 mmol) in THF (25 mL) was added withDEPC (0.25 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for 10′. Then[3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.376 g, 1.1 moleq) and a catalytic amount of TEA were added, then the reaction mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure, water (40 mL) was added to the residue that isextracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). Theseparated organic phase was anydrified over Na₂SO₄, evaporated todryness and the residue was purified by flash chromatography (1:1EtOAc:Petroleum ether) to afford a white solid (0.15 g) afterrecrystallization from ethyl ether. Yield=24%, ¹HNMR (DMSO, 200 MHz) δ1.08 (t, 3H, J=8), 3.37 (q, 2H, J=7.5), 4.44 (d, 2H, J06.1), 5.16 (s,1H), 6.09 (s, 1H), 7.32 (d, 1H), 7.46 (m, 5H), 7.53 (d, 1H), 7.62 (s,1H), 7.76 (dd, 2H), 7.86 (m, 2H), 8.78 (t, 1H); [M⁺¹] 522.51(C₂₅H₂₂F₄N₂O₄S requires 522.12).

Example 122-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 12

Acid 7 (295.76 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv.,277.5 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded100 mg of a beige solid. Yield=18.8% ¹HNMR (DMSO, 200 MHz) δ 1.12 (3H,t, J=7 Hz), 3.47 (2H, q), 4.48 (2H, d, J=6.4 Hz), 5.41 (1H, s), 6.25(1H, s), 7.34 (2H, m), 7.59 (1H, d, J=4 Hz), 7.84 (2H, d, J=8 Hz), 7.98(1H, bs), 8.28 (2H, d, J=8 Hz), 8.63 (1H, d, J=5 Hz), 8.91 (1H, bt)[M⁺¹] 530.1 (C₂₂H₁₉ClF₃N₃O₃S₂ requires 529.98).

Example 132-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of 2-chloro-6-pyrrolidin-1-yl-pyridine-4-carbonitrile 25A

A solution of 2,6-dichloropyridine-4-carbonitrile 24 (4 g, 23.5 mmol) inabs. EtOH (10 mL) was added with pyrrolidine (1.15 mL, 1 mol eq) and themixture was heated at 70° C. for 6 h. The solvent was removed underreduced pressure, water was added to the residue and the aqueous phasewas extracted with EtOAc (3×40 mL). The combined organic phase waswashed with brine (1×60 mL), dried over Na₂SO₄ and evaporated to afford25A as a pale yellow deliquescent solid (4.2 g, 20 mmol, 87% Yield).¹HNMR (DMSO, 400 MHz) δ 2.00 (m, 4H), 3.42 (m, 4H), 6.39 (s, 1H), 6.61(s, 1H).

Synthesis of2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile26A

(Bertelot et al., PCT, WO2010/141805 A1)

The nitrile 25A (2.1 g, 10.3 mmol), 4-trifluoromethylphenylboronic acid(2.15 g, 1.1 mol eq), palladium acetate (45 mg, 0.02 mol eq), cesiumcarbonate (6.5 g, 2 mol eq), and XPhos (190 mg, 0.04 mol eq) were mixed,placed under a nitrogen atmosphere and dioxane (10 mL) was added. Themixture was heated at 100° C. overnight. After cooling, the mixture wasfiltered through a celite pad, washed with dioxane (2×20 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography (9.5:0.5 petroleum ether:EtOAc) to afford 26A as a paleyellow semi-solid (2.8 g, 85% Yield). ¹HNMR (DMSO, 200 MHz) δ 1.93 (m,4H), 3.45 (m, 4H), 6.91 (s, 1H), 7.55 (s, 1H), 7.82 (d, 2H, J=8), 8.26(d, 2H, J=8.1).

Synthesis of[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A

A solution of nitrile 26A (2.8 g, 8.8 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.67 g, 2 mol eq) indiethyl ether (30 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 27A as a paleyellow oil (2.8 g, 87% yield). ¹HNMR (DMSO, 200 MHz) δ 1.91 (m, 4H),2.20 (bs, 2H), 3.37 (m, 4H), 3.70 (s, 2H), 6.48 (s, 1H), 7.20 (s, 1H),7.78 (d, 2H, J=8), 8.23 (d, 2H, J=8).

Preparation of2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 13

A solution of acid 4C (0.40 g, 1.45 mmol) in THF (20 mL) was added withDEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (0.51 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, water was added to theresidue that is extracted with EtOAc (3×25 mL) and washed with brine(1×40 mL). The separated organic phase was dried over Na₂SO₄, evaporatedto dryness and the residue was purified by flash chromatography (1:1EtOAc:Petroleum ether) to afford a white solid (0.18 g) aftercrystallization from ethyl ether. Yield=22%, ¹HNMR (DMSO, 200 MHz) δ1.95 (m, 4H), 2.95 (s, 3H), 3.46 (m, 4H), 4.36 (d, 2H), 5.12 (s, 1H),5.86 (s, 1H), 6.52 (s, 1H), 7.22 (s, 1H), 7.73 (d, 2H, JO 7.9),7.82-7.79 (m, 5H), 8.26 (d, 2H, J=7.8), 8.85 (t, 1H); [M⁺¹] 579.03(C₂₇H₂₆ClF₃N₄O₃S requires 578.13).

Example 142-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 14

Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (1.1 equiv., 353.47 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:petroleumether) afforded 140 mg of a pale yellow solid. Yield=23.6% ¹HNMR (DMSO,200 MHz) δ 1.09 (3H, t), 1.91 (4H, m), 3.38 (6H, m), 4.40 (2H, d), 5.17(1H, s), 6.11 (1H, d), 6.34 (1H, s), 7.19 (1H, s), 7.78 (6H, m), 8.28(2H, d), 8.80 (1H, bt) [M⁺¹] 593.9 (C₂₈H₂₈ClF₃N₄O₃S requires 593.06).

Example 152-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 15

Acid 7 (295.76 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (1.1 equiv., 353.47 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:petroleumether) afforded 150 mg of a pale yellow solid. Yield=25% ¹HNMR (DMSO,200 MHz) δ 1.07 (3H, t), 1.94 (4H, m), 3.41 (6H, m), 4.37 (2H, d), 5.39(1H, s), 6.21 (1H, s), 6.31 (1H, s), 7.20 (1H, s), 7.34 (1H, d, J=4.2Hz), 7.57 (1H, d, J=4 Hz), 7.91 (2H, d), 8.48 (2H, d), 8.75 (1H, bt)[M⁺¹] 599.9 (C₂₆H₂₆ClF₃N₄O₃S₂ requires 599.09).

Example 162-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of 2-chloro-6-morpholino-pyridine-4-carbonitrile 25B

2,6-dichloropyridine-4-carbonitrile 24 (4 gr, 23.13 mmol) was dissolvedin 100 ml of ethanol. To the solution were added TEA (1 equiv., 3.22ml), morpholine (1 equiv., 2 ml) and the mixture was stirred at 70° C.for 4 hours. (TLC AcOEt 3/petroleum ether 7). The solvent was evaporatedand the residue was dissolved with ethyl acetate, washed with water andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The crude was crystallized from ethyl acetate andpetroleum ether to give a beige solid. (4.6 g, 89% yield) ¹HNMR (DMSO,400 MHz) δ 3.58 (4H, m), 3.64 (4H, m), 7.10 (1H, s), 7.32 (1H, s)

Synthesis of2-morpholino-6-[4-(trifluoromethoxy)phenyl]pyridine-4-carbonitrile 26D

The carbonitrile 25B (2.3 g, 10.28 mmol) was dissolved in 80 ml ofdimethoxyethane. To the solution were added 40 ml of water, sodiumbicarbonate (3 equiv., 2.6 g), [4-(trifluoromethoxy)phenyl]boronic acid(1.2 equiv., 2.54 g) and the mixture was stirred at rt for 5′. Themixture was degassed and put under argon. A catalytic amount oftetrakispalladium was added and the mixture was heated at 100° C.overnight. The solvents were evaporated off and the residue wasdissolved with ethyl acetate, washed with water and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thecrude was crystallized from ethyl acetate and petroleum ether to give abeige solid. (2.0 g, 55.5% yield)¹HNMR (DMSO, 400 MHz) δ 3.61 (4H, m),3.72 (4H, m), 7.20 (1H, s), 7.79 (1H, s), 7.82 (2H, d, J=8 Hz), 8.35(2H, d, J=8 Hz)

Synthesis of[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27DThe nitrile 26D (2 g, 5.7 mmol) dissolved in 50 ml of diethyl ether wasadded dropwise to a mixture of LiAlH₄ (434 mg, 2 equiv.) in diethylether (60 mL) stirred at 0° C. Then the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was destroyed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was dried over Na₂SO₄ and evaporated to dryness to obtain1.3 g of the amine 27D as a yellow oil. Yield=65% ¹HNMR (DMSO, 400 MHz)δ 3.30 (2H, bs), 3.51 (4H, m), 3.76 (6H, m), 6.80 (1H, s), 7.29 (1H, s),7.42 (2H, d, J=8 Hz), 8.18 (2H, dd) Preparation of2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 16

A solution of acid 4C (0.40 g, 1.45 mmol) in THF (25 mL) was added withDEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27D(0.56 g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, the residue was suspended in EtOAcand washed with water and brine. After drying over Na₂SO₄, the separatedorganic phase was evaporated under reduced pressure and the residue waspurified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford apale yellow solid (0.24 g) after crystallization from a mixture ofdiethyl ether/petroleum ether. Yield=36%, ¹HNMR (DMSO, 200 MHz) δ 2.95(s, 3H), 3.55 (m, 4H), 3.70 (m, 4H), 4.40 (d, 2H, J=6), 5.12 (s, 1H),5.87 (s, 1H), 6.82 (s, 1H), 7.29 (s, 1H), 7.43 (d, 2H, J=8.2), 7.83-7.74(m, 4H), 8.17 (d, 2H, J=8), 8.86 (t, 1H); [M⁺¹] 611.03 (C₂₇H₂₆ClF₃N₄O₅Srequires 610.13).

Example 172-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 17

Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 27D(1.1 equiv., 388 mg) were added to the solution. The mixture was stirredat rt overnight then evaporated. The residue was dissolved in AcOEt (30ml) and washed with water (1×20 ml) and brine. The organic phase wasdried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:petroleumether) afforded 140 mg of a pale yellow solid. Yield=22% ¹HNMR (DMSO,400 MHz) δ 1.15 (3H, t), 3.38 (2H, q), 3.50 (4H, m), 3.70 (4H, m), 4.40(2H, d), 5.20 (1H, s), 6.18 (1H, s), 6.80 (1H, s), 7.20 (1H, s), 7.42(2H, d), 7.76 (2H, d), 7.82 (2H, d), 8.18 (2H, d), 8.89 (1H, bt) [M⁺¹]626.9 (C₂₈H₂₈ClF₃N₄O₅S requires 625.06).

Example 182-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]pyridine-4-carbonitrile26C

A solution of nitrile 25A (2.58 g, 12.5 mmol) in DME (90 mL) was addedwith 4-trifluoromethoxy phenyl boronic acid (2.64 g, 1.0 mol eq,) andNaHCO3 (3.15 g, 3 mol eq,) suspended in water (45 mL). The mixture wasdegassed under vacuum, then Palladium Tetrakis was added (catalyticamount) and the reaction was stirred at 100° C. under inert atmospherefor 12 h. The solvent was removed under reduced pressure and water wasadded to the residue (80 mL). The aqueous phase was extracted with EtOAc(3×60 mL) and the combined organic layer was washed with brine (80 mL)and dried over Na₂SO₄. The solvent was evaporated under vacuum to afford26C as deliquescent yellow solid (3.2 g, 9.6 mmol, 77% Yield). ¹HNMR(DMSO, 400 MHz) δ 1.85 (m, 4H), 3.42 (m, 4H), 6.38 (s, 1H), 7.08 (s,1H), 7.38 (d, 2H, J=8), 8.05 (d, 2H, J=8).

Synthesis of[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine27C

A solution of nitrile 26C (1.1 g, 3.3 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.25 g, 2 mol eq) indiethyl ether (30 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure and the residue was purifiedby flash chromatography (7:3 EtOAc:MeOH) to afford 27C as a pale yellowoil (0.87 g, 77% yield). ¹HNMR (DMSO, 400 MHz) δ 1.97 (m, 4H), 3.48 (m,4H), 3.68 (s, 2H), 4.15 (bs, 2H), 6.44 (s, 1H), 7.15 (s, 1H), 7.43 (d,2H, J=8), 8.17 (d, 2H, J=8).

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 18

A solution of acid 4B (0.21 g, 0.76 mmol) in THF (20 mL) was added withDEPC (0.15 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine27C (0.29 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (30 mL) and washed with water (50 mL) and brine. The separatedorganic phase, after drying over Na₂SO₄, was evaporated under reducedpressure and the residue was purified by flash chromatography (7:3Petroleum ether: EtOAc:) to afford a white solid after recrystallizationfrom diethyl ether (0.10 g, 22% Yield). ¹HNMR (DMSO, 200 MHz) δ 1.08 (t,3H, J=6.8 Hz), 1.94 (m, 4H), 3.39 (m, 2H), 3.44 (m, 4H), 4.37 (d, 2H,J=6), 5.13 (s, 1H), 6.11 (s, 1H), 6.42 (s, 1H), 7.11 (s, 1H), 7.46-7.38(m, 4H), 7.87 (m, 2H), 8.17 (d, 2H, J=9.6), 8.77 (t, 1H); [M⁺¹] 592.60(C₂₈H₂₈F₄N₄O₄S requires 592.17).

Example 19N-[[2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]prop-2-enamide

Synthesis of 2,6-bis[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile28A

2-6-dichloropyridine-4-carbonitrile 24 (3.7 g, 21.35 mmol) was dissolvedin 100 ml of dimethoxyethane. To the solution were added 70 ml of water,sodium bicarbonate (3 equiv., 5.38 g),[4-(trifluoromethyl)phenyl]boronic acid (2.4 equiv., 9.74 g) and themixture was stirred at rt for 5′. The mixture was degassed and put underargon. A catalytic amount of tetrakispalladium was added and the mixturewas heated at 100° C. overnight. The solvents were evaporated off andthe residue was dissolved with ethyl acetate, washed with water andbrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The crude was crystallized from ethyl acetate andpetroleum ether to give 28A as a beige solid. (2.5 g, 30% yield)

Synthesis of [2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine29A

The nitrile 28A (4.7 g, 12 mmol) dissolved in 50 ml of diethyl ether wasadded dropwise to a mixture of LiAlH₄ (912 mg, 2 equiv.) in diethylether (80 mL) stirred at 0° C. Then the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was destroyed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was dried over Na₂SO₄ and evaporated to dryness to obtain2.5 g of the amine 29A as yellow solid. Yield=52% ¹HNMR (DMSO, 400 MHz)δ 2.25 (2H, bs), 3.90 (2H, s), 7.90 (4H, d, J=8 Hz), 8.11 (2H, s), 8.40(4H, d, J=8 Hz)

Preparation ofN-[[2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]prop-2-enamideExample 19

Acid 4D (289.74 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.15 ml) and[2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 29A (1.1equiv., 400 mg) were added to the solution. The mixture was stirred atrt overnight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (3:7 EtOAc:petroleum ether) afforded140 mg of a white solid. Yield=21% ¹HNMR (DMSO, 400 MHz) δ 1.25 (3H, t),3.40 (2H, q), 4.60 (2H, d), 5.18 (1H, s), 6.18 (1H, s), 7.70 (2H, d),7.82 (2H, d), 7.86 (4H, d), 8.02 (2H, s), 8.40 (4H, d), 8.89 (1H, bt)[M⁺¹] 668.9 (C₃₁H₂₄ClF₆N₃O₃S requires 668.05).

Example 20N-[[2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)sulfonyl-methyl-amino]prop-2-enamide

Synthesis of 2,6-bis[4-(trifluoromethoxy)phenyl]pyridine-4-carbonitrile28B

A solution of 24 (4.0 g, 19.4 mmol) in DME (120 mL) was added with4-trifluoromethoxy phenyl boronic acid (1.1 mol eq, 4.2 g) and NaHCO3 (3mol eq, 4.9 g) suspended in water (90 mL). The mixture was degassedunder vacuum, then a catalytic amount of Tetrakispalladium was added andthe reaction was stirred at 100° C. under inert atmosphere for 12 h. Thesolvent was removed under reduced pressure and water was added to theresidue (100 mL). The aqueous phase was extracted with EtOAc (3×60 mL)and the combined organic layer was washed with brine (80 mL) and driedover Na₂SO₄. The solvent was evaporated under vacuum to afford 28B asdeep yellow solid after recrystallization from diethyl ether/petroleumether (68% Yield, 5.4 g, 13.8 mmol). ¹HNMR (DMSO, 400 MHz) δ 7.53 (d,4H, J=7.8), 8.38 (d, 4H, J=7.9), 8.48 (s, 2H).

Synthesis of [2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine29B

A solution of nitrile 28B (2.0 g, 5.1 mmol) in diethyl ether (40 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.39 g, 2 mol eq) indiethyl ether (50 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (40mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 29B as a paleorange oil (83% yield, 1.67 g, 4.2 mmol,). ¹HNMR (DMSO, 400 MHz) δ 3.321(bs, 2H), 4.01 (s, 2H), 7.50 (d, 4H, J=7.9), 7.98 (s, 2H), 8.31 (d, 4H,J=8).

Preparation ofN-[[2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)sulfonyl-methyl-amino]prop-2-enamideExample 20

A solution of acid 4C (0.50 g, 1.8 mmol) in THF (30 mL) was added withDEPC (0.35 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes.

Then [2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 29B(0.66 g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×50 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (6:4 EtOAc:Petroleumether) to afford a white solid (0.22 g) after crystallization fromdiethyl ether. Yield=18%, ¹HNMR (DMSO, 400 MHz) δ 2.96 (s, 3H), 4.55 (d,2H, J=4), 5.13 (s, 1H), 5.90 (s, 1H), 7.49 (d, 4H), 7.25 (d, 2H), 7.79(d, 2H), 7.96 (s, 2H), 8.31 (d, 4H, J=6.8), 9.00 (t, 1H); [M⁺¹] 686.02(C₃₀H₂₂ClF₆N₃O₅S requires 685.08).

Example 21(Z)-2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamide

Synthesis of methyl(2S)-2-[(4-fluorophenyl)sulfonylamino]-3-hydroxy-butanoate 9A

To L-threonine methyl ester hydrochloride 8 (4.8 g, 28.33 mmol)dissolved in methylene chloride (200 ml) was added with TEA (2 equiv.,7.89 ml) and in one portion 4-fluorobenzenesulfonyl chloride (1.0equiv., 28.79 mmol, 5.6 g). The reaction was refluxed for 4 hours. Thesolvent was evaporated and the crude was dissolved in AcOEt (100 ml) andwashed with water (1×80 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude residue by crystallization from diethyl ether and petroleum etherafforded 7.45 g of the white product 9A. Yield=90% ¹HNMR (DMSO, 200 MHz)δ 1.01 (3H, d, J=6.2 Hz), 3.39 (3H, s), 3.78 (1H, bs), 3.96 (1H, m),4.93 (1H, d, J=5.6 Hz), 7.39 (2H, m), 7.83 (2H, m), 8.12 (1H, bs)

Synthesis of methyl(2S)-2-[methyl-(4-fluorophenyl)sulfonyl-amino]-3-hydroxy-butanoate 10A

Compound 9A (5.5 g, 19 mmol) dissolved in DMF (15 ml) was added withK₂CO₃ (1.1 equiv., 2.75 g) and methyl iodide (1.1 equiv., 1.94 ml) andthe reaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 5 g of 10A as a semisolid.Yield=86%. ¹HNMR (DMSO, 200 MHz) δ 1.10 (3H, d, J=6.2 Hz), 2.94 (3H, s),3.46 (3H, s), 4.22 (1H, q, J=6.4 Hz), 4.39 (1H, d, J=5.2 Hz), 5.16 (1H,d, J=3.2 Hz), 7.40 (2H, m), 7.82 (2H, m)

Synthesis of (Z)-2-[methyl-(4-fluorophenyl)sulfonyl-amino]but-2-enoicacid 11A

Compound 10A (4.576 g, 15 mmol) dissolved in THF (30 ml) and water (10ml) was added with LiOH.H₂O (3 equiv., 1.88 g) and the reaction wasstirred at rt for 3 hours. The reaction was concentrated under vacuum.Water was added and then 10% HCl till precipitation of the acid. Theacid was extracted with ethyl acetate and the organic phase was washedwith Brine, dried over sodium sulfate and concentrated under vacuum togive 4 g of a white solid. Yield=93%. ¹HNMR (DMSO, 200 MHz) δ 1.08 (3H,t, J=7 Hz), 2.95 (3H, s), 4.02 (1H, q), 4.26 (1H, bs), 5.08 (1H, bs),7.43 (2H, m), 7.85 (2H, m), 12.84 (1H, bs). The intermediate acid (2 g,9.7 mmol) dissolved in pyridine (10 ml) was added dropwise with acetylchloride (1.4 equiv., 1.1 ml) at 0° C. and the reaction was then stirredat rt for 5 hours. The reaction was quenched by addition of 10% HCl andthen extracted with ethyl acetate. The organic phase was washed 2 timeswith water, with brine, dried over sodium sulfate and concentrated undervacuum. The crude product was crystallized from diethyl ether andpetroleum ether to give 1 g of a beige solid. Yield=50%. ¹HNMR (DMSO,200 MHz) δ 1.76 (3H, d, J=7 Hz), 2.95 (3H, s), 7.04 (1H, q, J=7 Hz),7.45 (2H, m), 7.83 (2H, m), 12.74 (1H, bs)

Preparation of(Z)-2-[methyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamideExample 21

Acid 11A (515 mg, 2.5 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.38 ml) and[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv.,737 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded200 mg of a pale yellow solid. Yield=15% ¹HNMR (DMSO, 200 MHz) δ 1.74(3H, d J=7.4 Hz), 3.06 (3H, s), 4.40 (2H, d, J=6 Hz), 6.83 (1H, q, J=7Hz), 7.44 (5H, m), 7.83 (3H, m), 8.18 (2H, d, J=8.2 Hz), 8.59 (1H, d,J=5.2 Hz), 8.70 (1H, bt) [M⁺¹] 524.3 (C₂₄H₂₁F₄N₃O₄S requires 523.50).

Example 22(Z)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamide

Synthesis of methyl(2S)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-3-hydroxy-butanoate 10B

Compound 9A (1 g, 3.0 mmol) dissolved in DMF (10 ml) was added withK₂CO₃ (1.1 equiv., 456 mg) and ethyl iodide (1.1 equiv., 0.316 ml) andthe reaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 895 mg of a semisolid.Yield=93%. ¹HNMR (DMSO, 200 MHz) δ 1.13 (3H, d, J=6.2 Hz), 1.26 (3H, t,J=7 Hz), 3.32 (3H, s), 3.41 (2H, q, J=7.8 Hz), 4.02 (1H, bs), 4.23 (1H,m), 5.13 (1H, d, J=4.6 Hz), 7.42 (2H, m), 7.84 (2H, m)

Synthesis of (Z)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]but-2-enoicacid 11B

Compound 10B (895 mg, 2.8 mmol) dissolved in THF (10 ml) and water (5ml) was added with LiOH.H₂O (3 equiv., 352 mg) and the reaction wasstirred at rt 3 hours. The reaction was concentrated under vacuum. Waterwas added and 10% HCl till precipitation of the acid. The acid wasextracted with ethyl acetate and the organic phase was washed withBrine, dried over sodium sulfate and concentrated under vacuum to give770 mg of a white solid. Yield=96%. ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, t,J=7.2 Hz), 1.17 (3H, t, J=7 Hz), 3.34 (2H, q, J=7.8 Hz), 4.02 (1H, m),4.21 (1H, bs), 5.13 (1H, bs), 7.43 (2H, m), 7.85 (2H, m), 12.84 (1H,bs). The intermediate acid (1.6 g, 7 mmol) dissolved in pyridine (10 ml)was added dropwise with acetyl chloride (1.4 equiv., 0.8 ml) at 0° C.and the reaction was then stirred at rt for 5 hours. The reaction wasquenched by addition of 10% HCl and then extracted with ethyl acetate.The organic phase was washed 2 times with water, with brine, dried oversodium sulfate and concentrated under vacuum. The crude product wascrystallized from diethyl ether and petroleum ether to give 650 mg of11B as a beige solid. Yield=32%. ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, t,J=7.4 Hz), 1.80 (3H, d J=7.2 Hz), 3.47 (2H, m), 7.18 (1H, q, J=6.6 Hz),7.43 (2H, m), 7.83 (2H, m), 12.64 (1H, bs)

Preparation of(Z)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamideExample 22

Acid 11B (574 mg, 2 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.3 ml) and[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv.,590 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (1:1 EtOAc:petroleum ether) afforded195 mg of a white solid. Yield=18% ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, t,J=7.2 Hz), 1.46 (3H, d J=7.4 Hz), 3.43 (2H, q, J=7 Hz), 4.40 (2H, d, J=6Hz), 6.83 (1H, q, J=7 Hz), 7.25 (1H, dd, J=6.4 Hz), 7.42 (4H, m), 7.85(3H, m), 8.18 (2H, d, J=8.2 Hz), 8.60 (1H, d, J=5 Hz), 8.74 (1H, bt)[M⁺¹] 538.1 (C₂₅H₂₃F₄N₃O₄S requires 537.53).

Example 23(Z)-2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]but-2-enamide

Synthesis of methyl(2S)-2-[(4-chlorophenyl)sulfonylamino]-3-hydroxy-butanoate 9C

L-Threonine methyl ester hydrochloride 8 (4.8 g, 28.33 mmol) dissolvedin methylene chloride (200 ml) was added with TEA (2 equiv., 7.89 ml)and in one portion 4-chlorobenzenesulfonyl chloride (1.0 equiv., 5.97g). The reaction was refluxed for 4 hours. The solvent was evaporatedand the crude was dissolved in AcOEt (100 ml) and washed with water(1×80 ml) and brine. The organic phase was dried over sodium sulfate andconcentrated under vacuum. The purification of the crude residue bycrystallization from diethyl ether and petroleum ether afforded 9.6 g ofthe white product. Yield=98% ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.4Hz), 3.40 (3H, s), 3.78 (1H, d, J=4 Hz), 3.95 (1H, m), 4.96 (1H, d,J=5.6 Hz), 7.64 (2H, m), 7.77 (2H, m), 8.12 (1H, bs)

Synthesis of methyl(2S)-2-[methyl-(4-chlorophenyl)sulfonyl-amino]-3-hydroxy-butanoate 10C

Compound 9C (3, 8.7 mmol) dissolved in DMF (10 ml) was added with K₂CO₃(1.1 equiv., 1.3) and methyl iodide (1.1 equiv., 0.88 ml) and thereaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 2.85 g of 10C as asemisolid. Yield=93.7%.

¹HNMR (DMSO, 200 MHz) δ 1.08 (3H, d, J=6.4 Hz), 2.94 (3H, s), 3.46 (3H,s), 4.22 (1H, q), 4.41 (1H, d), 5.20 (1H, d), 7.65 (2H, m), 7.74 (2H, m)

Synthesis of (Z)-2-[methyl-(4-chlorophenyl)sulfonyl-amino]but-2-enoicacid 11C

Compound 10C (2.85 g, 8.15 mmol) dissolved in THF (30 ml) and water (10ml) was added with LiOH.H₂O (3 equiv., 1.03 g) and the reaction wasstirred at rt for 3 hours. The reaction was concentrated under vacuum.Water was added and then 10% HCl till precipitation of the acid. Theacid was extracted with ethyl acetate and the organic phase was washedwith Brine, dried over sodium sulfate and concentrated under vacuum togive 2.5 g of a white solid. Yield=91%. ¹HNMR (DMSO, 200 MHz) δ 1.08(3H, t, J=7 Hz), 2.73 (3H, s), 4.02 (1H, q), 4.26 (1H, bs), 5.02 (1H,bs), 7.63 (2H, m), 7.79 (2H, m), 12.09 (1H, bs) The intermediate acid(2.5 g, 7.45 mmol) dissolved in pyridine (10 ml) was added dropwise withacetyl chloride (1.4 equiv., 0.83 ml) at 0° C. and the reaction was thenstirred at 50° C. for 5 hours. The reaction was quenched by addition of10% HCl and then extracted with ethyl acetate. The organic phase waswashed 2 times with water, with brine, dried over sodium sulfate andconcentrated under vacuum. The crude product was crystallized fromdiethyl ether and petroleum ether to give 870 mg of 11C as a beigesolid. Yield=40%. ¹HNMR (DMSO, 200 MHz) δ 1.77 (3H, d, J=7.2 Hz), 3.32(3H, s), 7.04 (1H, q, J=6.8 Hz), 7.64 (2H, m), 7.77 (2H, m), 12.74 (1H,bs) Preparation of(Z)-2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]but-2-enamideExample 23

Acid 11C (868 mg, 3 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.5 ml) and [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine23A (1.1 equiv., 837 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:petroleumether) afforded 200 mg of a pale yellow solid. Yield=13% ¹HNMR (DMSO,200 MHz) δ 1.47 (3H, d, J=7 Hz), 3.01 (3H, s), 4.27 (2H, d, J=6.2 Hz),6.68 (1H, q), 7.60 (12H, m), 8.64 (1H, bt) [M⁺¹] 523.2 (C₂₅H₂₂ClF₃N₂O₃Srequires 522.97).

Example 24(Z)-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]but-2-enamide

Synthesis of methyl(2S)-2-[ethyl-(4-chlorophenyl)sulfonyl-amino]-3-hydroxy-butanoate 10D

Compound 9C (3 g, 8.94 mmol) dissolved in DMF (15 ml) was added withK₂CO₃ (1.1 equiv., 1.36 g) and ethyl iodide (1.1 equiv., 1 ml) and thereaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 2.8 g of a semisolid.Yield=97%. ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, d, J=6.2 Hz), 1.26 (3H, t,J=7 Hz), 3.32 (3H, s), 3.34 (2H, m), 4.02 (1H, bs), 4.23 (1H, m), 5.14(1H, d, J=4.4 Hz), 7.62 (2H, m), 7.76 (2H, m)

Synthesis of (Z)-2-[ethyl-(4-chlorophenyl)sulfonyl-amino]but-2-enoicacid 11D

Compound 10D (2.08 g, 6.2 mmol) dissolved in THF (20 ml) and water (5ml) was added with LiOH.H₂O (3 equiv., 783 mg) and the reaction wasstirred at rt 3 hours. The reaction was concentrated under vacuum. Waterwas added and 10% HCl till precipitation of the acid. The acid wasextracted with ethyl acetate and the organic phase was washed withBrine, dried over sodium sulfate and concentrated under vacuum to give1.75 g of a white solid. Yield=88%. ¹HNMR (DMSO, 200 MHz) δ 1.02 (3H, t,J=6.4 Hz), 1.17 (3H, t, J=7 Hz), 3.31 (2H, m), 4.02 (1H, m), 4.21 (1H,bs), 5.13 (1H, bs), 7.63 (2H, m), 7.78 (2H, m), 12.88 (1H, bs). Theintermediate acid (1.75 g, 5.44 mmol) dissolved in pyridine (10 ml) wasadded dropwise with acetyl chloride (1.4 equiv., 0.6 ml) at 0° C. andthe reaction was then stirred at rt for 5 hours. The reaction wasquenched by addition of 10% HCl and then extracted with ethyl acetate.The organic phase was washed 2 times with water, with brine, dried oversodium sulfate and concentrated under vacuum. The crude product wascrystallized from diethyl ether and petroleum ether to give 600 mg of11D as a beige solid. Yield=36%. ¹HNMR (DMSO, 200 MHz) δ 1.00 (3H, t,J=7.2 Hz), 1.80 (3H, d, J=7 Hz), 3.45 (2H, m), 7.20 (1H, q), 7.63 (2H,d, J=8.6 Hz), 7.76 (2H, d, J=8.6 Hz), 12.64 (1H, bs)

Preparation of(Z)-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]but-2-enamideExample 24

Acid 11D (600 mg, 1.97 mmol) was dissolved in 10 ml of THF and at rtDEPC (1.1 equiv, 0.3 ml) and[3-[4-(trifluoromethyl)phenyl]phenyl]methanamine 23A (1.1 equiv., 550mg) were added to the solution. The mixture was stirred at rt overnightthen evaporated. The residue was dissolved in AcOEt (30 ml) and washedwith water (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the crude bychromatographic column (3:7 EtOAc:petroleum ether) afforded 150 mg of awhite solid. Yield=14% ¹HNMR (DMSO, 200 MHz) δ 0.98 (3H, t, J=7.2 Hz),1.53 (3H, d J=7.4 Hz), 3.36 (2H, q, J=7 Hz), 4.28 (2H, d, J=6 Hz), 6.80(1H, q, J=7 Hz), 7.8 (12H, m), 8.60 (1H, bt) [M⁺¹] 537.1(C₂₆H₂₄ClF₃N₂O₃S requires 536.99).

Example 251-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Synthesis of methyl1-[(4-fluorophenyl)sulfonylamino]cyclopropanecarboxylate 13A

A suspension of methyl-1-aminocyclopropane carboxylate hydrochloride 12(0.6 g, 3.96 mmol) in CH₂Cl₂ (60 mL) was added with TEA (1.1 mol eq, 0.6mL) and the mixture was stirred at r.t. for 10 minutes. Then4-fluorobenzensulfonyl chloride (1 mol eq, 0.77 g) and additional TEA(1.1 mol eq) were added and the solution was heated at 60° C. overnight.The solvent was removed under reduced pressure, water was added to theresidue (100 mL) and the aqueous phase was extracted with EtOAc (3×40mL). The combined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 13A as transparent oil (1.07 g, 99%yield). ¹HNMR (DMSO, 200 MHz) δ 1.17 (m, 2H), 1.27 (m, 2H), 3.32 (s,3H), 7.46 (t, 2H, J=9), 7.80 (m, 2H), 8.78 (bs, 1H).

Synthesis of methyl1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxylate 14A

A solution of 13A (1 g, 3.67 mmol) in DMF (15 mL) was added with an.K₂CO₃ (1.5 mol eq, 0.76 g) and, after few minutes, 2-iodoethane (1.2 moleq, 0.45 ml) was added and the mixture was heated at 50° C. for 12 h.The solvent was removed under reduced pressure, water was added to theresidue (60 mL) and the aqueous phase was extracted with EtOAc (3×30mL). The combined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 14A as a pale yellow oil (1.1 g, 98%yield). ¹HNMR (DMSO, 200 MHz) δ 1.095 (t, 3H, J=8), 4.43 (bs, 4H), 2.88(s, 3H), 3.32 (m, 2H), 7.42 (t, 2H, J=8.2), 7.87 (m, 2H).

Synthesis of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxylic acid 15A

A solution of 14A (1.3 g, 4.33 mmol) in dioxane (40 mL) was added with10% NaOH aq. solution (20 mL) and the mixture was heated at 50° C.overnight. The organic solvent was removed under reduced pressure andthe aqueous phase was acidified with 10% HCl. The solid formed wascollected by filtration, washed with water (2×20 mL) and dried to afford15A as white solid (1.0 g, 81% yield). ¹HNMR (DMSO, 200 MHz) δ 1.10 (t,3H, J=7.2), 1.65 (bs, 4H), 7.39 (m, 2H), 7.84 (m, 2H), 12.90 (bs, 1H).

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 25

Acid 15A (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC(1.1 equiv, 0.17 ml) and[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv.,277.5 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. he residue was dissolved in AcOEt (30 ml) andwashed with water (1×20 ml) and brine. The organic phase was dried oversodium sulfate and concentrated under vacuum. The purification of thecrude by chromatographic column (1:1 EtOAc:Petroleum ether) afforded 140mg of a white solid. Yield=26.8% ¹HNMR (DMSO, 400 MHz) δ 1.09 (2H, bs),1.23 (3H, t, J=7.2 Hz), 1.40 (2H, bs), 3.40 (2H, q, J=6.8 Hz), 4.41 (2H,bs), 7.26 (1H, dd), 7.42 (2H, t, J=8.8 Hz), 7.87 (4H, m), 7.98 (1H, bs),8.30 (3H, bd), 8.64 (1H, dd, J=4.8 Hz) [M⁺¹] 521.9 (C₂₅H₂₃F₄N₃O₃Srequires 521.53).

Example 261-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 26

A solution of acid 15A (0.5 g, 1.7 mmol) in THF (30 mL) was added withDEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.51 g, 1.1mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, the residue was suspended in EtOAc (40mL) and washed with water (50 mL) and brine. The separated organic phasewas dried over Na₂SO₄ and evaporated under reduced pressure and theresidue was purified by flash chromatography (7:3 EtOAc:Petroleum ether)to afford a white solid (0.18 g) after crystallization from diethylether. Yield=30%, ¹HNMR (DMSO, 200 MHz) δ 1.09 (bs, 2H), 1.22 (t, 3H,J=8), 1.26 (bs, 2H), 3.41 (bs, 2H), 4.43 (d, 2H, J=6); 7.27 (d, 1H,J=4), 7.46-7.42 (m, 4H), 7.90 (m, 3H), 8.23 (m, 3H), 8.61 (d, 1H,J=5.2). [M⁺¹] 537.53 (C₂₅H₂₃F₄N₃O₄S requires 537.13).

Example 271-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Synthesis of methyl1-[(4-chlorophenyl)sulfonylamino]cyclopropanecarboxylate 13B

To methyl 1-aminocyclopropanecarboxylate hydrochloride 12 (500 mg, 3.298mmol) dissolved in methylene chloride (20 ml) was added with TEA (2equiv., 1 ml) and in one portion 4-chlorobenzenesulfonyl chloride (1.0equiv., 765 mg). The reaction was refluxed for 4 hours. The solvent wasevaporated and the crude was dissolved in EtOAc (50 ml) and washed withwater (1×30 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the cruderesidue by crystallization from diethyl ether and petroleum etherafforded 800 mg of the white product 13B. Yield=84% ¹HNMR (DMSO, 200MHz) δ 1.16 (2H, m), 1.30 (2H, m), 3.32 (3H, s), 7.70 (4H, m), 8.87 (1H,bs)

Synthesis of methyl1-[(4-chlorophenyl)sulfonyl-ethyl-amino]cyclopropanecarboxylate 14B

Compound 13B (800 mg, 2.76 mmol) dissolved in DMF (10 ml) was added withK₂CO₃ (1.1 equiv., 420 mg) and ethyl iodide (1.1 equiv., 0.3 ml) and thereaction was stirred at rt overnight. The reaction was diluted withethyl acetate and washed several times with water and finally withBrine. The organic phase was dried over sodium sulfate and concentratedunder vacuum. The purification of the crude residue by crystallizationfrom ethyl ether and petroleum ether afforded 750 mg of 14B as asemisolid. Yield=85.5%. ¹HNMR (DMSO, 200 MHz) δ 1.096 (3H, t, J=7.2 Hz),1.17 (2H, m), 1.43 (2H, bs), 3.34 (2H, m), 3.43 (3H, s), 7.68 (2H, m),7.79 (2H, m)

Synthesis of1-[(4-chlorophenyl)sulfonyl-ethyl-amino]cyclopropanecarboxylic acid 15B

Compound 14B (750 mg, 2.36 mmol) dissolved in THF (10 ml) and water (5ml) was added with LiOH.H₂O (3 equiv., 297 mg) and the reaction wasstirred at rt 3 hours. The reaction was concentrated under vacuum. Waterwas added and 10% HCl till precipitation of the acid. The acid wasextracted with ethyl acetate and the organic phase was washed withBrine, dried over sodium sulfate and concentrated under vacuum to give650 mg of 15B as a white solid. Yield=90%. ¹HNMR (DMSO, 200 MHz) δ 1.06(3H, t, J=7.2 Hz), 1.38 (2H, m), 1.35 (2H, bs), 3.33 (2H, m), 7.43 (2H,m), 7.77 (2H, m), 12.46 (1H, bs)

Preparation of1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 27

Acid 15B (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC(1.1 equiv, 0.17 ml) and[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv.,295 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 ml)and washed with water (1×20 ml) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded100 mg of a white solid. Yield=18% ¹HNMR (DMSO, 200 MHz) δ 1.12 (2H,bs), 1.22 (3H, t, J=7.2 Hz), 1.40 (2H, bs), 3.40 (2H, q, J=4.8 Hz), 4.41(2H, d, J=5.4 Hz), 7.26 (1H, dd, J=3.8 Hz), 7.49 (2H, d, J=8 Hz), 7.65(2H, dd, J=8.6 Hz), 7.84 (2H, dd, J=6.8 Hz, J′=1.6 Hz), 7.90 (1H, bs),8.20 (2H, dd, J=6.8 Hz, J′=1.8 Hz), 8.28 (1H, t), 8.59 (1H, d, J=5.2 Hz)[M⁺¹] 553.9 (C₂₅H₂₃ClF₃N₃O₄S requires 553.98).

Example 281-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Synthesis of methyl1-[(5-chloro-2-thienyl)sulfonylamino]cyclopropanecarboxylate 16

A suspension of methyl-1-aminocyclopropen carboxylate hydrochloride 12(1 g, 1.43 mmol) in CH₂Cl₂ (100 mL) was added with TEA (1.1 mol eq, 1.01mL) and the mixture was stirred at r.t. for 10 minutes. Then5-chloro-thiophene-2-sulfonyl chloride (1 mol eq, 1.43 g) and additionalTEA (1.1 mol eq) were added and the solution was heated at 50° C.overnight. The solvent was removed under reduced pressure, water wasadded to the residue (100 mL) and the aqueous phase was extracted withEtOAc (3×50 mL). The combined organic phases were dried over Na₂SO₄ andevaporated under reduced pressure to afford 16 as a pale orange oil(quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.23 (m, 2H), 1.35 (m,2H), 1.98 (s, 3H), 7.23 (d, 1H, J=4), 7.73 (d, 1H, J=3.9), 9.12 (bs,1H).

Synthesis methyl1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]cyclopropanecarboxylate 17

A solution of 16 (2 g, 6.7 mmol) in DMF (20 mL) was added with an. K₂CO₃(1.5 mol eq, 1.4 g) and, after few minutes, 2-iodoethane (1.2 mol eq,0.84 ml) was added and the mixture was heated at 50° C. for 4 h. Thesolvent was removed under reduced pressure, water was added to theresidue (100 mL) and the aqueous phase was extracted with EtOAc (3×50mL). The combined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 17 as a pale yellow oil (2.1 g, 95%yield). ¹HNMR (DMSO, 200 MHz) δ 1.18 (m, 2H), 1.25 (t, 3H), 1.37 (m,2H), 1.98 (s, 3H), 3.45 (m, 2H), 7.28 (d, 1H, J=4), 7.78 (d, 1H, J=3.9)

Synthesis of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]cyclopropanecarboxylic acid18

A solution of 17 (2.1 g, 6.5 mmol) in dioxane (20 mL) was added with 10%NaOH aq. solution (20 mL) and the mixture was heated at 50° C.overnight. The organic solvent was removed under reduced pressure andthe aqueous phase was acidified with 10% HCl.

The solid formed was collected by filtration, washed with water (2×20mL) and dried to afford 18 as a pale yellow solid (1.6 g, 85% yield).¹HNMR (DMSO, 200 MHz) δ 1.13 (t, 3H, J=7.4), 1.39 (bs, 4H), 3.36 (m,2H), 7.25 (d, 2H, J=4.1), 7.52 (d, 2H, H=4)), 12.90 (bs, 1H).

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 28

A solution of acid 18 (0.50 g, 1.62 mmol) in THF (25 mL) was added withDEPC (0.32 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for 10′. Then[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.47 g, 1.1mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, water (40 mL) was added to the residuethat was extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL).The separated organic phase was dried over Na₂SO₄, evaporated to drynessand the residue was purified by flash chromatography (1:1EtOAc:Petroleum ether) to afford a pale yellow oil (0.31 g). Yield=35%,¹HNMR (DMSO, 200 MHz) δ 1.22 (t, 3H), 1.40 (bs, 2H), 1.61 (bs, 2H), 4.16(q, 2H), 4.42 (d, 2H, J=6.1), 7.26 (m, 2H), 7.46 (d, 2H, J=8), 7.6 (dd,1H), 7.87 (s, 1H), 8.21 (d, 2H, J=7.9), 8.25 (t, 1H), 8.60 (d, 1H, J=4);[M⁺¹] 560.01 (C₂₃H₂₁ClF₃N₃O₄S₂ requires 559.06).

Example 291-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 29

A solution of acid 15A (0.30 g, 1.45 mmol) in THF (20 mL) was added withDEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[3-[4-(trifluoromethyl)phenyl]phenyl]methanamine 23A (0.29 g, 1.1 moleq) and a catalytic amount of TEA were added, then the reaction mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure, water was added to the residue that is extracted withEtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organicphase was dried over Na₂SO₄, evaporated to dryness and the residue waspurified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford awhite solid (0.13 g) after crystallization from ethyl ether. Yield=25%,¹HNMR (DMSO, 200 MHz) δ 1.055 (t, 2H), 1.17 (t, 3H, J=7), 1.28 (bs, 2H),3.43 (q, 2H), 4.29 (d, 2H, J=6), 7.25 (d, 2H), 7.40 (m, 3H), 7.47 (m,3H), 7.87-7.83 (m, 4H), 8.15 (t, 1H); [M⁺¹] 520.54 (C₂₆H₂₄F₄N₂O₃Srequires 520.14).

Example 301-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide

Preparation of1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 30

Acid 15B (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC(1.1 equiv, 0.17 ml) and[3-[4-(trifluoromethyl)phenyl]phenyl]methanamine 23A (1.1 equiv., 276mg) were added to the solution. The mixture was stirred at rt overnightthen evaporated. The residue was dissolved in AcOEt (30 ml) and washedwith water (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the crude bychromatographic column (3:7 EtOAc:Petroleum ether) afforded 90 mg of awhite solid. Yield=17% ¹HNMR (DMSO, 200 MHz) δ 1.11 (2H, bm), 1.18 (3H,t, J=7 Hz), 1.38 (2H, bs), 3.40 (2H, bm), 4.38 (2H, d, J=5.8 Hz), 7.30(1H, dd), 7.46 (1H, t, J=7.6 Hz), 7.64 (4H, m), 7.85 (6H, m), 7.90 (1H,bs), 8.10 (1H, t) [M⁺¹] 537.3 (C₂₆H₂₄ClF₃N₂O₃S requires 536.99).

Example 311-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 31

A solution of acid 15A (0.30 g, 1.8 mmol) in THF (20 mL) was added withDEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for 10 minutes. Then[3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.308 g, 1.1 moleq) and a catalytic amount of TEA were added, then the reaction mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure, the residue was suspended in EtOAc (45 mL) and washedwith water (50 mL) and brine. The separated organic phase was dried overan. Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford awhite solid (0.15 g). Yield=28%, ¹HNMR (DMSO, 200 MHz) δ 1.08 (m, 2H),1.20 (t, 3H, J=8), 1.38 (bs, 2H), 3.42 (q, 2H), 4.38 (d, 2H, J=5.6),7.27 (d, 1H, J=4), 7.46-7.39 (m, 6H), 7.55 (d, 1H), 7.59 (s, 1H), 7.78(m, 2H), 7.87 (m, 2H), 8.08 (t, 1H). [M⁺¹] 536.54 (C₂₆H₂₄F₄N₂O₄Srequires 536.14).

Example 321-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Synthesis of 1-[(4-fluorophenyl)sulfonylamino]cyclopropanecarboxylicacid 15C

Compound 13A (645 mg, 2.36 mmol) dissolved in THF (10 ml) and water (5ml) was added with LiOH.H₂O (3 equiv., 297 mg) and the reaction wasstirred at rt 3 hours. The reaction was concentrated under vacuum. Waterwas added and 10% HCl till precipitation of the acid. The acid wasextracted with ethyl acetate and the organic phase was washed withBrine, dried over sodium sulfate and concentrated under vacuum to give600 mg of 15C as a white solid. Yield=98%. ¹HNMR (DMSO, 200 MHz) δ 1.38(2H, m), 1.35 (2H, bs), 7.42 (2H, m), 7.80 (2H, m), 8.80 (1H, bs), 12.46(1H, bs) Preparation of1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 32

A solution of acid 15C (0.50 g, 1.75 mmol) in THF (25 mL) was added withDEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for 5′. Then[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (0.61 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, water (40 mL) was added tothe residue that is extracted with EtOAc (3×25 mL) and washed with brine(1×40 mL). The separated organic phase was dried over Na₂SO₄, evaporatedto dryness and the residue was purified by flash chromatography (1:1EtOAc:Petroleum ether) to afford a pale orange solid (0.21 g) aftercrystallization from a mixture of ethyl ether/petroleum ether.Yield=22%, ¹HNMR (DMSO, 200 MHz) δ 0.71 (m, 2H), 1.09 (m, 2H9, 1.96 (m,4H), 3.38 (m, 4H), 4.18 (d, 2H, J=6.1), 6.33 (s, 1H), 6.46 (s, 1H),7.47-7.38 (m, 4H), 7.88-7.80 (m, 4H), 8.37 (t, 1H), 8.71 (bs, 1H); [M⁺¹]562.58 (C₂₇H₂₆F₄N₄O₃S requires 562.16).

Example 331-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 33

Acid 15C (260 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC(1.1 equiv, 0.17 ml) and[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine27C (1.1 equiv., 371 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inEtOAc (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:Petroleumether) afforded 130 mg of a white solid. Yield=22% ¹HNMR (DMSO, 200 MHz)δ 0.71 (2H, bm), 1.08 (2H, bm), 1.92 (4H, m), 3.47 (4H, m), 4.29 (2H, d,J=5.6 Hz), 6.41 (1H, s), 7.09 (1H, s), 7.45 (4H, m), 7.82 (2H, m), 8.17(2H, d, J=9 Hz), 8.38 (1H, t), 8.71 (1H, bs) [M⁺¹] 579.4 (C₂₇H₂₆F₄N₄O₄Srequires 578.58).

Example 341-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 34

A solution of acid 18 (0.24 g, 0.76 mmol) in THF (20 mL) was added withDEPC (0.15 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for several minutes. Then[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (0.27 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc and washed with water (1×50 mL) and brine. After drying overNa₂SO₄, the separated organic phase was evaporated under reducedpressure and the residue was purified by flash chromatography (1:1EtOAc:Petroleum ether) to afford a pale yellow solid (0.18 g) aftercrystallization from a mixture of ethyl ether/petroleum ether.Yield=38%, ¹HNMR (DMSO, 200 MHz) δ 0.86 (t, 3H), 1.21 (m, 4H), 1.91 (m,4H), 3.42 (m, 6H), 4.21 (d, 2H, J=6.2), 6.26 (s, 1H), 6.45 (s, 1H), 7.27(d, 1H, J=4), 7.58 (d, 1H, J=3.8), 7.82 (d, 2H, J=7.8), 8.21 (d, 2H,J=8.1), 8.41 (t, 1H); [M⁺¹] 613.11 (C₂₇H₂₈ClF₃N₄O₃S₂ requires 612.12).

Example 352-[(3,4-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl(2S)-2-[(3,4-difluorophenyl)sulfonylamino]-3-hydroxy-propanoate 2G

A suspension of L-serine-methyl ester hydrochloride (1.5 g, 9.5 mmol) inCH₂Cl₂ (70 mL) was added with TEA (1.1 mol eq, 1.45 mL) and the mixturewas stirred at r.t. for 10 minutes. Then 3,4-difluorobenzensulfonylchloride (1 mol eq, 2.0 g) and additional TEA (1.1 mol eq) were addedand the solution hated at 60° C. overnight. The solvent was removedunder reduced pressure, water was added to the residue (100 mL) and theaqueous phase extracted with EtOAc (3×40 mL). The recombined organicphases were dried over Na₂SO₄ and evaporated to reduced pressure. Theresidue was recrystallized from ethylic ether to afford 2G as a paleorange solid (2.85 g, 94% yield). ¹HNMR (DMSO, 200 MHz) δ 3.45 (s, 3H),3.54 (m, 2H), 3.95 (m, 1H), 5.01 (t, 1H), 7.66 (m, 2H), 7.88 (m, 1H),8.46 (d, 1H, J=8).

Synthesis of methyl(2S)-2-[(3,4-difluorophenyl)sulfonyl-ethyl-amino]-3-hydroxy-propanoate3G

A solution of 2G (2.85 g, 8.8 mmol) in DMF (20 mL) was added with an.K₂CO₃ (1.5 mol eq, 1.83 g) and, after few minutes, 2-iodoethane (1.2 moleq, 1.09 mL) was added and the mixture heated at 50° C. for 12 h. Thesolvent was removed under reduced pressure, water was added to theresidue (150 mL) and the aqueous phase extracted with EtOAc (3×60 mL).The recombined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 3G as a pale yellow oil (2.8 g, 90%yield). ¹HNMR (DMSO, 200 MHz) δ 1.15 (m, 3H), 1.98 (s, 3H), 3.08 (m,2H), 4.04 (q, 2H, J=8), 4.58 (t, 1H), 5.15 (bm, 1H), 7.71 (m, 2H), 7.94(m, 1H).

Synthesis of 2-[ethyl-(3,4-difluorophenyl)sulfonyl-amino]prop-2-enoicacid 4G

A solution of 3G (2.8 g, 7.9 mmol) in dioxane (30 mL) was added with 20%NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 5 h. Theorganic solvent was removed under reduced pressure and the aqueous phaseacidified with 10% HCl and extracted with CH₂Cl₂ (3×30 mL). Therecombined organic phases were anhydrified using Na₂SO₄, evaporatedunder reduced pressure and then the resulting residue purified by flashchromatography (100% EtOAc) to obtain 4G as white solid (1 g, 44%yield). ¹HNMR (DMSO, 200 MHz) δ 1.07 (t, 3H), 3.42 (q, 2H), 5.78 (s,1H), 6.36 (s, 1H), 7.67 (m, 2H), 7.87 (m, 1H), 13.02 (bs, 1H).

Preparation of2-[ethyl-(3,4-difluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 35

Acid 4G (500 mg, 1.7 mmol) was dissolved in 20 ml of THF and at rt DEPC(1.3 equiv, 0.34 ml) and[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv.,476 mg) were added to the solution. The mixture was stirred at rtovernight then evaporated. The residue was dissolved in AcOEt (30 mL)and washed with water (1×20 mL) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded120 mg of a white solid. Yield=24% ¹HNMR (DMSO, 200 MHz) δ 1.09 (3H, t,J=7.2 Hz), 3.45 (2H, q, J=6.8 Hz), 4.51 (2H, d, J=6 Hz), 5.31 (1H, s),6.17 (1H, s), 7.38 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.68 (2H, t, J=8.8Hz), 7.83 (d, 3H), 8.02 (s, 1H), 8.32 (d, 2H, J=7.8), 8.67 (d, 1H,J=5.8), 8.93 (t, 1H). [M⁺¹] 525.11 (C₂₄H₂₀F₅N₃O₃S requires 524.98).

Example 362-[(3-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of methyl(2S)-2-[(3-fluorophenyl)sulfonylamino]-3-hydroxy-propanoate 2F

A suspension of L-serine-methyl ester hydrochloride (1.6 g, 10.3 mmol)in CH₂Cl₂ (70 mL) was added with TEA (1.1 mol eq, 1.6 mL) and themixture was stirred at r.t. for 10 minutes. Then 3-fluorobenzensulfonylchloride (1 mol eq, 2.0 g) and additional TEA (1.1 mol eq) were addedand the solution hated at 60° C. overnight. The solvent was removedunder reduced pressure, water was added to the residue (100 mL) and theaqueous phase extracted with EtOAc (3×40 mL). The recombined organicphases were dried over Na₂SO₄ and evaporated to reduced pressure. Theresidue was recrystallized from ethylic ether to afford 2F as a paleyellow solid (2.80 g, 95% yield). ¹HNMR (DMSO, 200 MHz) δ 3.41 (s, 3H),3.48 (m, 2H), 4.01 (m, 1H), 5.20 (t, 1H), 7.58 (m, 2H), 7.81 (m, 2H),8.52 (d, 1H, J=8).

Synthesis of methyl(2S)-2-[(3-fluorophenyl)sulfonyl-ethyl-amino]-3-hydroxy-propanoate 3F

A solution of 2F (3.0 g, 10.8 mmol) in DMF (15 mL) was added with an.K₂CO₃ (1.5 mol eq, 2.24 g) and, after few minutes, 2-iodoethane (1.2 moleq, 1.33 mL) was added and the mixture heated at 50° C. for 12 h. Thesolvent was removed under reduced pressure, water was added to theresidue (150 mL) and the aqueous phase extracted with EtOAc (4×50 mL).The recombined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 3F as a pale orange viscous oil (3.2 g,95% yield). ¹HNMR (DMSO, 200 MHz) δ 1.15 (m, 3H), 2.00 (s, 3H), 3.79 (q,2H, J=8), 4.06 (t, 1H), 4.59 (t, 1H), 5.18 (m, 2H), 7.94 (m, 4H).

Synthesis of 2-[ethyl-(3-fluorophenyl)sulfonyl-amino]prop-2-enoic acid4F

A solution of 3F (3.0 g, 9.8 mmol) in dioxane (30 mL) was added with 20%NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 5 h. Theorganic solvent was removed under reduced pressure and the aqueous phaseacidified with 10% HCl. The solid formed was filtered under vacuum,washed with cold water (1×50 mL) and dried to afford 4F as white solid(650 mg, 25% yield). ¹HNMR (DMSO, 200 MHz) δ 1.11 (t, 3H, J=7.7), 3.43(q, 2H), 5.78 (s, 1H), 6.36 (s, 1H), 7.69 (m, 2H), 7.84 (m, 2H), 12.98(bs, 1H).

Preparation of2-[ethyl-(3-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 36

Acid 4F (330 mg, 1.2 mmol) was dissolved in 15 ml of THF and at rt DEPC(1.3 equiv, 0.23 mL) and[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 molequiv., 335 mg) were added to the solution. The mixture was stirred atrt overnight then evaporated. The residue was dissolved in AcOEt (30 mL)and washed with water (1×20 mL) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded100 mg of a white solid. Yield=20% ¹HNMR (DMSO, 200 MHz) δ 1.09 (3H, t,J=7.2 Hz), 3.44 (2H, q, J=6.8 Hz), 4.50 (2H, d, J=6 Hz), 5.21 (1H, s),6.14 (1H, s), 7.34 (1H, dd, J=4.8), 7.65 (m, 4H), 7.81 (d, 2H, J=7.9),8.01 (s, 1H), 8.31 (d, 2H, J=7.8), 8.65 (d, 1H, J=5.8), 8.92 (t, 1H).[M⁺¹] 507.62 (C₂₄H₂₁F₄N₃O₃S requires 507.50).

Example 37N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide

Synthesis of 2-chloro-6-(N,N′-dimethylamino)-pyridine-4-carbonitrile 25C

Compound 24 (1.5 g, 8.7 mmol) was added with hexamethylphosphoramide(1.56 mL, 1 mol eq) and the mixture was heated at 120° C. for 12 h. Thereaction was cooled and then water was added (300 mL). The solid formedwas collected by filtration and washed three times with water (3×30 mL)then dried to afford 25C as a pale yellow solid (1.28 g, 82% Yield).¹HNMR (DMSO, 200 MHz) δ 3.04 (s, 6H), 7.10 (s, 1H)), 8.23 (s, 1H).

Synthesis of2-(N,N′-dimethylamino)-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile26E

The nitrile 25C (2.0 g, 11.1 mmol), 4-trifluoromethylphenylboronic acid(2.32 g, 1.1 mol eq), palladium acetate (50 mg, 0.02 mol eq), cesiumcarbonate (7.23 g, 2 mol eq), and XPhos (210 mg, 0.04 mol eq) weremixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added.The mixture was heated at 100° C. for 3 h. After cooling, the mixturewas filtered through a celite pad, washed with dioxane (2×20 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography (9.5/0.5 petroleum ether/EtOAc) to afford 26E as a paleyellow solid (2.2 g, 68% Yield). ¹HNMR (DMSO, 200 MHz) δ 3.13 (s, 6H),7.12 (s, 1H), 7.58 (s, 1H), 7.82 (d, 2H, J=7.7), 8.30 (d, 2H, J=7.8).

Synthesis of[2-(N,N′-dimethylamino)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E

A solution of nitrile 26E (2.2 g, 7.6 mmol) in diethyl ether (50 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.58 g, 2 mol eq) indiethyl ether (50 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 27E as a paleyellow oil (2.13 g, 95% yield). ¹HNMR (DMSO, 200 MHz) δ 3.08 (s, 6H),3.97 (s, 2H), 6.66 (s, 1H), 7.24 (s, 1H), 7.77 (d, 2H, J=7.5), 8.24 (d,2H, J=8).

Preparation ofN-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamideExample 37

Acid 4B (830 mg, 3.0 mmol) was dissolved in 25 ml of THF and at rt, thenDEPC (1.3 mol equiv, 0.59 mL) and[2-(N,N′-dimethylamino)-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E (1.1 mol equiv., 970 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. Water was added to the residue(100 mL) and extracted with EtOAc (3×30 mL). The organic phases weredried over sodium sulfate and evaporated to dryness. The residue waspurified by chromatographic column (8/2 EtOAc/petroleum ether) to afford260 mg of a white solid. Yield=16% ¹HNMR (DMSO, 400 MHz) δ 1.06 (t, 3H,J=7.7), 3.07 (s, 6H), 3.38 (q, 2H, J=7.6), 4.38 (d, 2H, J=8), 5.10 (s,1H), 6.10 (s, 1H), 6.59 (s, 1H), 7.21 (s, 1H), 7.47 (m, 2H), 7.78 (d,2H, J=7.6), 7.84 (m, 2H), 8.23 (d, 2H, J=8), 8.79 (t, 1H). [M⁺¹] 550.57(C₂₆H₂₆F₄N₄O₃S requires 550.81).

Example 382-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 38

A solution of acid 4B (0.15 g, 0.53 mmol) in THF (10 mL) was added withDEPC (0.10 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (0.17 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, water was added to theresidue that is extracted with EtOAc (3×25 mL) and washed with brine(1×40 mL). The separated organic phase was dried over Na₂SO₄, evaporatedto dryness and the residue was purified by flash chromatography (1/1EtOAc/Petroleum ether) to afford a white solid (90 mg) aftercrystallization from ethyl ether. Yield=32%. ¹HNMR (DMSO, 200 MHz) δ1.092 (t, 3H, J=5.6), 1.95 (m, 4H), 3.4-3.46 (m, 6H), 4.39 (d, 2H, J=6),5.13 (s, 1H), 6.12 (s, 1H), 6.47 (s, 1H), 7.20 (s, 1H), 7.51 (t, 2H,J=7.9), 7.80-7.90 (m, 4H), 8.27 (d, 2H, J=8.1), 8.78 (bt, 1H). [M⁺¹]576.28 (C₂₈H₂₈F₄N₄O₃S requires 576.60).

Example 392-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 39

A solution of acid 7I (0.16 g, 0.54 mmol) in THF (12 mL) was added wasadded DEPC (0.10 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-(N,N′-dimethylamino)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E (0.175 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, water was added to theresidue that is extracted with EtOAc (3×20 mL) and washed with brine(1×30 mL). The separated organic phase was dried over Na₂SO₄, evaporatedto dryness and the residue was purified by flash chromatography (1/1EtOAc/Petroleum ether) to afford a white solid (60 mg) aftercrystallization from ethyl ether. Yield=19%. ¹HNMR (DMSO, 200 MHz) δ1.12 (t, 3H, J=7.2), 3.09 (s, 6H), 3.46 (m, 2H), 4.39 (d, 2H, J=6.5),5.39 (s, 1H), 6.23 (s, 1H), 6.64 (s, 1H), 7.20 (s, 1H), 7.36 (d, 1H,J=4), 7.62 (d, 1H, J=3.9), 7.81 (d, 2H, J=7.8), 8.26 (d, 2H, J=7.9),8.81 (bt, 1H). [M⁺¹] 572.85 (C₂₄H₂₄ClF₃N₄O₃S₂ requires 573.05).

Example 402-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of 2-chloro-6-methoxy-pyridine-4-carbonitrile 25F

A solution of compound 24 (2.0 g, 11.6 mmol) in methanol (20 mL) wasadded with sodium methoxyde (628 mg, 1 mol eq) and the mixture washeated at 60° C. for 6 h. The reaction was cooled, evaporated to drynessand then water was added (300 mL). The aqueous phase was extracted withEtOAc (3×25 mL) and the recombined organic phases were dried over sodiumsulfate and evaporated under reduced pressure to afford 25F astransparent viscous oil (1.95 g, quantitative yield). ¹HNMR (DMSO, 200MHz) δ 3.80 (s, 3H), 7.17 (s, 1H), 7.90 (s, 1H).

Synthesis of2-methoxy-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile 26I

The nitrile 25F (2.3 g, 13.8 mmol), 4-trifluoromethylphenylboronic acid(2.61 g, 1.1 mol eq), palladium acetate (62 mg, 0.02 mol eq), cesiumcarbonate (8.97 g, 2 mol eq), and XPhos (260 mg, 0.04 mol eq) weremixed, placed under a nitrogen atmosphere and dioxane (10 mL) was added.The mixture was heated at 100° C. for 4 h. After cooling, the mixturewas filtered through a celite pad, washed with dioxane (2×30 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography (9:1 petroleum ether:EtOAc) to afford 26I as a paleyellow solid (840 mg, 25% Yield). ¹HNMR (DMSO, 200 MHz) δ 4.03 (s, 3H),7.46 (s, 1H), 7.90 (d, 2H, J=7.8), 8.17 (s, 1H), 8.40 (d, 2H, J=8).

Synthesis of[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I

A solution of nitrile 26I (420 mg, 1.5 mmol) in diethyl ether (30 mL)was added in small amounts to a mixture of LiAlH₄ (115 mg, 2 mol eq) indiethyl ether (20 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 27I as a paleyellow oil (370 mg, 88% yield). ¹HNMR (DMSO, 200 MHz) δ 4.13 (s, 3H),4.22 (s, 2H), 7.56 (s, 1H), 7.88 (d, 2H, J=7.8), 8.26 (s, 1H), 8.51 (d,2H, J=8).

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 40

A solution of acid 4B (0.31 g, 1.1 mmol) in THF (20 mL) was added withDEPC (0.22 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I (0.36g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (1/1 EtOAc/Petroleumether) to afford a white solid (180 mg) after crystallization from ethylether. Yield=30%. ¹HNMR (DMSO, 200 MHz) δ 1.08 (t, 3H, J=6), 3.39 (m,2H), 3.95 (s, 3H), 4.45 (d, 2H, J=6.2), 5.14 (s, 1H), 6.13 (s, 1H), 6.79(s, 1H), 7.47 (t, 2H, J=8.2), 7.64 (s, 1H), 7.85 (m, 4H), 8.31 (d, 2H,J=7.8), 8.84 (bt, 1H). [M⁺¹] 537.05 (C₂₅H₂₃F₄N₃O₄S requires 537.53).

Example 41N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-(ethyl(2-thienylsulfonyl)amino)prop-2-enamide

Synthesis of methyl (2S)-3-hydroxy-2-(2-thienylsulfonylamino)propanoate5H

A suspension of L-serine-methyl ester hydrochloride (3.0 g, 19.3 mmol)in CH₂Cl₂ (80 mL) was added with TEA (1.1 mol eq, 2.9 mL) and themixture was stirred at r.t. for 10 minutes. Then 2-thiophen-sulphonylchloride (1 mol eq, 3.52 g) and additional TEA (1.1 mol eq) were addedand the solution hated at 60° C. overnight. The solvent was removedunder reduced pressure, water was added to the residue (100 mL) and theaqueous phase extracted with EtOAc (3×40 mL). The recombined organicphases were dried over Na₂SO₄ and evaporated under reduced pressure toafford 5H as white solid (4.9 g, 95% yield). ¹HNMR (DMSO, 200 MHz) δ3.61 (s, 2H), 3.82 (t, 2H, J=6.3), 4.14 (m, 1H), 4.62 (t, 1H), 5.25 (t,1H), 7.21 (m, 1H), 7.75 (dd, 1H, J=2.1), 7.96 (dd, 1H, J=1.9), 8.23 (d,1H).

Synthesis of methyl(2S)-2-(ethyl(2-thienylsulfonyl)amino)-3-hydroxy-propanoate 6H

A solution of 5H (4.9 g, 18.6 mmol) in DMF (20 mL) was added with an.K₂CO₃ (1.5 mol eq, 3.85 g) and, after few minutes, 2-iodoethane (1.2 moleq, 2.29 mL) was added and the mixture heated at 50° C. for 12 h. Thesolvent was removed under reduced pressure, water was added to theresidue (150 mL) and the aqueous phase extracted with EtOAc (4×50 mL).The recombined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 6H as a pale yellow oil (2.13 g, 44%yield). ¹HNMR (DMSO, 200 MHz) δ 1.17 (t, 3H, J=6.2), 3.34 (q, 2H,J06.3), 3.49 (s, 2H), 3.76 (t, 2H, J=6.3), 4.04 (m, 1H), 4.50 (t, 1H),5.18 (t, 1H), 7.18 (m, 1H), 7.65 (dd, 1H, J=2.1), 7.96 (dd, 1H, J=1.9).

Synthesis of 2-(ethyl(2-thienylsulfonyl)amino)prop-2-enoic acid 7H

A solution of 6H (2.13 g, 9.8 mmol) in dioxane (30 mL) was added with20% NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 5 h.The organic solvent was removed under reduced pressure and the aqueousphase acidified with 10% HCl. The solid formed was filtered undervacuum, washed with cold water (2×25 mL) and dried to afford 7H as whitesolid (135 mg, 42% yield). ¹HNMR (DMSO, 200 MHz) δ 1.02 (t, 3H, J=7.7),3.39 (q, 2H, J=6.3), 5.67 (s, 1H), 6.34 (s, 1H), 7.21 (m, 1H), 7.62 (dd,1H, J=2.1), 8.00 (dd, 1H, J=1.9), 13.01 (bs, 1H).

Preparation ofN-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-(ethyl(2-thienylsulfonyl)amino)prop-2-enamideExample 41

A solution of acid 7H (0.30 g, 1.15 mmol) in THF (20 mL) was added withDEPC (0.23 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-(N,N′-dimethylamino)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E (0.371 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, water was added to theresidue that is extracted with EtOAc (3×30 mL) and washed with brine(1×40 mL). The separated organic phase was dried over Na₂SO₄, evaporatedto dryness and the residue was purified by flash chromatography (6/4EtOAc/Petroleum ether) to afford a white solid (0.22 g) aftercrystallization from ethyl ether. Yield=36%. ¹HNMR (DMSO, 200 MHz) δ1.12 (t, 3H, J=6), 3.09 (s, 6H), 3.44 (m, 2H), 4.40 (d, 2H, J=4.2), 5.15(s, 1H), 6.21 (s, 1H), 6.66 (s, 1H), 7.27 (m, 2H), 7.68 (dd, 1H, J=1.8),7.77 (d, 2H, J=7.9), 8.06 (dd, 1H, J=2.1), 8.27 (d, 2H, J=7.8), 8.78(bt, 1H). [M⁺¹] 538.02 (C₂₄H₂₅F₃N₄O₃S₂ requires 538.60).

Example 422-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of2-morpholino-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile 26B

The nitrile 25B (3.2 g, 14.4 mmol), 4-trifluoromethylphenylboronic acid(3.01 g, 1 mol eq), palladium acetate (65 mg, 0.02 mol eq), cesiumcarbonate (9.38 g, 2 mol eq), and XPhos (265 mg, 0.04 mol eq) weremixed, placed under a nitrogen atmosphere and dioxane (12 mL) was added.The mixture was heated at 100° C. overnight. After cooling, the mixturewas filtered through a celite pad, washed with dioxane (2×30 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography (7/3 Petroleum ether/EtOAc) to afford 26B as yellow solid(1.33 g, 40% Yield). ¹HNMR (DMSO, 400 MHz) δ 3.63 (m, 4H, J=1.9), 3.74(m, 4H, J=2), 7.38 (s, 1H), 7.74 (s, 1H), 7.84 (d, 2H, J=8.1), 8.32 (d,2H, J=8).

Synthesis of[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27B

A solution of nitrile 26B (1.33 g, 4 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (305 mg, 2 mol eq) indiethyl ether (20 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 27B as a paleyellow oil (1.34 g, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 3.54(m, 4H), 3.76 (m, 6H), 6.87 (s, 1H), 7.38 (s, 1H), 7.81 (d, 2H, J=8),8.27 (d, 2H, J=7.9).

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 42

A solution of acid 4B (0.40 g, 1.46 mmol) in THF (20 mL) was added withDEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27B(530 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (6/4 EtOAc/Petroleumether) to afford a white solid (95 mg) after crystallization from ethylether. Yield=12%. ¹HNMR (DMSO, 200 MHz) δ 1.087 (t, 3H, J=7.8), 3.39 (q,2H, J=7.6), 3.55 (m, 4H), 3.71 (m, 4H), 4.42 (d, 2H, J=6.2), 5.13 (s,1H), 6.12 (s, 1H), 6.85 (s, 1H), 7.35 (s, 1H), 7.47 (t, 2H, J=8),7.83-7.90 (m, 4H), 8.26 (d, 2H, J=8), 8.80 (bt, 1H). [M⁺¹] 592.33(C₂₈H₂₈F₄N₄O₄S requires 592.60).

Example 432-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 43

A solution of acid 7I (0.14 g, 0.47 mmol) in THF (15 mL) was added withDEPC (0.092 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27B(0.175 g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×20 mL) and washed with brine (1×30 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (1/1 EtOAc/Petroleumether) to afford a white solid (90 mg) after crystallization from ethylether. Yield=32%. ¹HNMR (DMSO, 200 MHz) δ 1.12 (t, 3H, J=7.2), 3.47 (m,2H), 3.54 (m, 4H), 3.72 (m, 4H), 4.41 (d, 2H, J=6.2), 5.39 (s, 1H), 6.23(s, 1H), 6.81 (s, 1H), 7.34 (m, 2H), 7.60 (d, 1H, J=4), 7.81 (d, 2H,J=8.1), 8.25 (d, 2H, J=8.2), 8.82 (t, 1H). [M⁺¹] 614.98(C₂₆H₂₆ClF₃N₄O₄S₂ requires 615.09).

Example 442-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Synthesis of 2-chloro-6-isopropoxy-pyridine-4-carbonitrile 25H

A mixture of NaH 60% (05 g, 1.1 mol eq) in 2-isopropanol (15 mL) cooledat 0° C., was added in small portions with the nitrile 24 (2 g, 11.6mmol). The reaction mixture was then heated at 60° C. for 5 h. Water wasadded (30 ml) and the aqueous phase was extracted with EtOAc (3×20 mL).The recombined organic phases were dried over sodium sulfate andevaporated under reduced pressure to afford 25H as a pale yellow viscousoil (1.82 g, 80% Yield).

¹HNMR (DMSO, 200 MHz) δ 1.31 (d, 6H, J=4), 5.18 (m, 1\H), 6.71 (s, 1H),7.36 (s, 1H).

Synthesis of2-isopropoxy-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile 26M

The nitrile 25H (1.25 g, 6.4 mmol), 4-trifluoromethylphenylboronic acid(1.34 g, 1 mol eq), palladium acetate (29 mg, 0.02 mol eq), cesiumcarbonate (4.16 g, 2 mol eq), and XPhos (137 mg, 0.04 mol eq) weremixed, placed under a nitrogen atmosphere and dioxane (8 mL) was added.The mixture was heated at 100° C. for 4 h. After cooling, the mixturewas filtered through a celite pad, washed with dioxane (2×30 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography (9.5/0.5 Petroleum ether/EtOAc) to afford 26M as yellowsolid (0.65 g, 36% Yield). ¹HNMR (DMSO, 200 MHz) δ 1.37 (d, 6H, J=3.9),5.15 (m, 1H), 6.7 (s, 1H), 7.32 (s, 1H), 7.87 (d, 2H, J=7.8), 8.33 (d,2H, J=8).

Synthesis of[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27M

A solution of nitrile 26M (0.65 g, 2.14 mmol) in diethyl ether (30 mL)was added in small amounts to a mixture of LiAlH₄ (163 mg, 2 mol eq) indiethyl ether (20 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (40 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 27M as a yellowoil (0.56 g, 86% yield). ¹HNMR (DMSO, 400 MHz) δ 1.28 (d, 6H, J=5.8),3.74 (s, 2H), 5.41 (m, 1H), 6.21 (s, 1H), 6.75 (s, 1H), 7.84 (d, 2H,J=7.8), 8.27 (d, 2H, J=8).

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 44

A solution of acid 4B (300 g, 1.09 mmol) in THF (15 mL) was added withDEPC (0.21 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27M(370 mg, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (3/7 EtOAc/Petroleumether) to afford a white solid (100 mg) after crystallization from ethylether. Yield=18%. ¹HNMR (DMSO, 400 MHz) δ 1.08 (t, 3H, J=7.4), 1.26 (d,6H, J=6.2), 3.39 (q, 2H), 4.40 (d, 2H, J=7.9), 5.13 (s, 1H), 5.39 (m,1H), 6.12 (s, 1H), 6.65 (s, 1H), 7.42 (t, 3H, J=4), 7.56 (s, 1H), 7.86(m, 4H), 8.23 (d, 2H, J=8), 8.79 (t, 1H). [M⁺¹] 565.02 (C₂₇H₂₇F₄N₃O₄Srequires 565.58).

Example 45N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide

Preparation ofN-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamideExample 45

Acid 15B (400 mg, 1.4 mmol) was dissolved in 20 ml of THF and at rt,then DEPC (1.3 mol equiv, 0.27 mL) and[2-(N,N′-dimethylamino)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E (1.1 mol equiv., 450 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. Water was added to the residue(80 mL) and extracted with EtOAc (3×30 mL). The organic phases weredried over sodium sulfate and evaporated to dryness. The residue waspurified by chromatographic column (8/2 EtOAc/petroleum ether) to afford220 mg of a white solid. Yield=28%. ¹HNMR (DMSO, 200 MHz) δ 1.08 (bs,2H), 1.22 (t, 3H, J=8.1), 1.26 (bs, 2H), 3.11 (s, 6H), 3.42 (m, 2H),4.36 (bd, 2H), 6.63 (s, 1H), 7.2 (s, 1H), 7.42 (t, 2H, J=10), 7.88 (m,4H), 8.27 (m, 3H). [M⁺¹] 564.59 (C₂₇H₂₈F₄N₄O₃S requires 564.29).

Example 461-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 46

Acid 18 (0.3 g, 1.09 mmol) was dissolved in 15 ml of THF and at rt DEPC(1.3 equiv, 0.21 mL) and[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 molequiv., 0.37 g) were added to the solution. The mixture was stirred atrt overnight then evaporated. The residue was dissolved in AcOEt (30 mL)and washed with water (1×20 mL) and brine. The organic phase was driedover sodium sulfate and concentrated under vacuum. The purification ofthe crude by chromatographic column (EtOAc 3/petroleum ether 7) afforded100 mg of a white solid. Yield=18% ¹HNMR (DMSO, 200 MHz) δ 1.24 (m, 5H),1.35 (m, 2H), 3.45 (m, 2H), 4.44 (d, 2H, J=6.2), 7.26 (m, 3H), 6.61 (d,1H, J=2.1), 7.88 (d, 2H, J=7.8), 7.94 (s, 1H), 8.31 (d, 3H, J=8), 8.64(d, 1H, J=4.1). [M⁺¹] 543.95 (C₂₃H₂₁ClF₃N₃O₃S₂ requires 544.01).

Example 471-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 47

A solution of acid 18 (0.20 g, 0.65 mmol) in THF (15 mL) was added withDEPC (0.13 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for 10 minutes. Then[3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.19 g, 1.1 moleq) and a catalytic amount of TEA were added, then the reaction mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure, the residue was suspended in EtOAc (45 mL) and washedwith water (40 mL) and brine. The separated organic phase was dried overan. Na₂SO₄ and evaporated under reduced pressure. The residue waspurified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford awhite solid (0.2 g). Yield=59%, ¹HNMR (DMSO, 200 MHz) δ 1.23 (m, 5H),1.41 (m, 2H), 3.36 (m, 2H), 4.39 (d, 2H, J=6.1), 7.25 (m, 2H), 7.45 (m,4H), 7.57 (m, 2H), 7.79 (d, 2H, J=7.9), 8.09 (t, 1H). [M⁺¹] 559.31(C₂₄H₂₂ClF₃N₂O₄S₂ requires 559.02).

Example 481-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 48

A solution of acid 15B (0.2 g, 0.69 mmol) in THF (20 mL) was added withDEPC (0.135 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I(0.214 g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (1/1 EtOAc/Petroleumether) to afford a white solid (170 mg) after crystallization from ethylether. Yield=49%. ¹HNMR (DMSO, 200 MHz) δ 1.08 (m, 2H), 1.22 (t, 3H,J=6.5), 1.25 (m, 2H), 3.42 (m, 2H), 3.96 (s, 3H), 4.39 (d, 2H, J=6.2),6.75 (s, 1H), 7.41 (t, 2H, J=7.8), 7.61 (s, 1H), 7.91 (m, 4H), 8.32 (m,3H). [M⁺¹] 551.65 (C₂₆H₂₅F₄N₃O₄S requires 551.55).

Example 491-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 49

A solution of acid 15B (0.16 g, 0.55 mmol) in THF (15 mL) was added withDEPC (0.11 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27M(0.19 g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (1/1 EtOAc/Petroleumether) to afford a pale yellow solid (100 mg) after crystallization fromethyl ether. Yield=31%. ¹HNMR (DMSO, 200 MHz) δ 0.83 (m, 3H), 1.12 (m,4H), 1.36 (d, 6H, J=6.1), 3.43 (m, 2H), 4.37 (d, 2H, J=6), 5.40 (m, 1H),6.64 (s, 1H), 7.41 (t, 2H), 7.56 (s, 1H), 7.89 (m, 4H), 8.27 (m, 3H)[M⁺¹] 579.88 (C₂₈H₂₉F₄N₃O₄S requires 579.61).

Example 501-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 50

A solution of acid 18 (0.3 g, 0.97 mmol) in THF (15 mL) was added withDEPC (0.19 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27I (0.22g, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×30 mL) and washed with brine (1×30 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (1/1 EtOAc/Petroleumether) to afford a white solid (110 mg) after crystallization from ethylether. Yield=26%. ¹HNMR (DMSO, 400 MHz) δ 1.21 (t, 5H, J=6.2), 1.41 (m,2H), 3.54 (m, 2H), 3.94 (s, 3H), 4.18 (bs, 2H), 6.70 (s, 1H), 7.25 (d,1H, J=2.1), 7.57 (d, 2H, J=2.3), 7.84 (d, 2H, J=8), 8.27 (m, 3H). [M⁺¹]574.66 (C₂₄H₂₃ClF₃N₃O₄S₂ requires 574.04).

Example 511-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 51

A solution of acid 15B (0.3 g, 1.04 mmol) in THF (15 mL) was added withDEPC (0.20 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27A (0.36 g, 1.1 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, water was added to theresidue that is extracted with EtOAc (3×35 mL) and washed with brine(1×40 mL). The separated organic phase was dried over Na₂SO₄, evaporatedto dryness and the residue was purified by flash chromatography (4/6EtOAc/Petroleum ether) to afford a white solid (105 mg) aftercrystallization from ethyl ether. Yield=18%. ¹HNMR (DMSO, 200 MHz) δ1.08 (m, 2H), 1.22 (t, 3H, J=6), 1.26 (m, 2H), 1.96 (m, 4H), 3.47 (m,6H), 4.34 (d, 2H, J=6.3), 6.43 (s, 1H), 7.17 (s, 1H), 7.46 (t, 2H, J=8),7.86 (m, 4H), 8.20 (t, 1H), 8.27 (d, 2H, J=8). [M⁺¹] 590.11(C₂₉H₃₀F₄N₄O₃S requires 590.63).

Example 52N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide

Synthesis of2-chloro-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile 25G

A solution of compound 24 (2.5 g, 14.5 mmol) in abs. ethanol (30 mL) wasadded with sodium ethoxyde (1.08 mg, 1.1 mol eq) and the mixture washeated at 60° C. overnight. The reaction was cooled, evaporated todryness and then water was added (300 mL). The aqueous phase wasextracted with EtOAc (3×35 mL) and the recombined organic phases weredried over sodium sulfate and evaporated under reduced pressure toafford 25G as a pale yellow oil (1.1 g, 45% Yield). ¹HNMR (DMSO, 200MHz) δ 1.23 (t, 3H, J=6.2), 4.24 (q, 2H, J=6.3), 7.07 (s, 1H), 7.38 (s,1H).

Synthesis of2-ethoxy-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile 26 L

The nitrile 25G (1.1 g, 6.07 mmol), 4-trifluoromethylphenylboronic acid(1.15 g, 1 mol eq), palladium acetate (27 mg, 0.02 mol eq), cesiumcarbonate (3.95 g, 2 mol eq), and XPhos (116 mg, 0.04 mol eq) weremixed, placed under a nitrogen atmosphere and dioxane (7 mL) was added.The mixture was heated at 100° C. for 3 h. After cooling, the mixturewas filtered through a celite pad, washed with dioxane (2×30 mL) andconcentrated under reduced pressure. The residue was purified by flashchromatography (9.5/0.5 petroleum ether/EtOAc) to afford 26L as a paleyellow solid (620 mg, 40% Yield). ¹HNMR (DMSO, 200 MHz) δ 1.38 (t, 3H,J=6.2), 4.5 (q, 2H, J=6.3), 7.40 (s, 1H), 7.89 (d, 2H, J=8), 8.14 (s,1H), 8.36 (d, 2H, H=8).

Synthesis of[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27L

A solution of nitrile 26L (620 mg, 2.1 mmol) in diethyl ether (20 mL)was added in small amounts to a mixture of LiAlH₄ (162 mg, 2 mol eq) indiethyl ether (20 mL) stirred at 0° C. After the addition was completed,the mixture was stirred at room temperature overnight. The excess ofLiAlH₄ was destroyed at 0° C. by addition of small amount of water (30mL), the solid formed was filtered off and the organic filtrate wasseparated, washed with brine (50 mL) and dried over Na₂SO₄. The organicphase was evaporated under reduced pressure to afford 27L as a paleyellow oil (650 mg, quantitative yield). ¹HNMR (DMSO, 200 MHz) δ 1.34(t, 3H, J=6.2), 3.30 (bs, 2H), 4.44 (q, 2H, J=6.3), 6.80 (s, 1H), 7.64(s, 1H), 7.85 (d, 2H, J=7.8), 8.30 (d, 2H, J=8).

Preparation ofN-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamideExample 52

A solution of acid 15B (260 mg, 0.91 mmol) in THF (20 mL) was added withDEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27L (300mg, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×35 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (4/6 EtOAc/Petroleumether) to afford a white solid (120 mg) after crystallization from ethylether. Yield=23%. ¹HNMR (DMSO, 200 MHz) δ 1.05 (t, 4H), 1.25 (t, 3H,J=6.3), 1.40 (t, 4H), 3.39 (m, 2H), 4.45 (m, 4H), 6.7 (s, 1H), 7.42 (t,2H), 7.59 (s, 1H), 7.86 (m, 3H), 8.25 (m, 3H). [M⁺¹] 565.42(C₂₇H₂₇F₄N₃O₄S requires 565.58).

Example 531-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Synthesis of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 53

A solution of acid 18 (281 mg, 0.90 mmol) in THF (20 mL) was added withDEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature several minutes. Then[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27L (300mg, 1.1 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, water was added to the residue thatis extracted with EtOAc (3×35 mL) and washed with brine (1×40 mL). Theseparated organic phase was dried over Na₂SO₄, evaporated to dryness andthe residue was purified by flash chromatography (4/6 EtOAc/Petroleumether) to afford a white solid (130 mg) after crystallization from ethylether. Yield=25%. ¹HNMR (DMSO, 200 MHz) δ 1.23 (m, 4H), 1.4 (m, 6H),3.41 (m, 2H), 4.41 (m, 4H), 6.67 (s, 1H), 7.27 (d, 1H, J=3.8), 7.58 (m,2H), 7.86 (d, 2H, J=8), 8.28 (m, 3H). [M⁺¹] 587.80 (C₂₅H₂₅ClF₃N₃O₄S₂requires 588.06).

Example 542-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[1-oxido-2-[4-(trifluoromethyl)phenyl]pyridin-1-ium-4-yl]methyl]prop-2-enamide

Preparation of2-[ethyl-(4-fluorophenyl)sulfonyl-amino]N-[[1-oxido-2-[4-(trifluoromethyl)phenyl]pyridin-1-ium-4-yl]methyl]prop-2-enamideExample 54

3-Chloro perbenzoic acid (1.5 mol eq, 100 mg) was added to a solution ofExample 1 (200 mg, 0.39 mmol) in CHCl₃ (10 mL) and the mixture wasstirred at r.t. for 24 hours. Then 10% water solution of K₂CO₃ was addedto wash the organic phase that was then dried over Na₂SO₄ and evaporatedunder reduced pressure. The resulting residue was purified by flashchromatography (EtOAc 6/petroleum ether 4) to obtain a white solid (60mg, 29% yield). ¹HNMR (DMSO, 200 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.40(2H, q, J=6.8 Hz), 4.40 (2H, d, J=6 Hz), 5.14 (1H, s), 6.10 (1H, s),7.36 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.46 (2H, t, J=8.8 Hz), 7.63 (1H, d,J=2.2 Hz), 7.83 (4H, m), 8.05 (2H, d, J=8 Hz), 8.34 (1H, d, J=6.8 Hz),8.82 (1H, bt) [M⁺¹] 524.6 (C₂₄H₂₁F₄N₃O₄S requires 523.50).

Example 552-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamide

Preparation of2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamideExample 55

Acid 7I (665 mg, 2 mmol) was dissolved in 10 ml of THF and at rt DEPC(1.1 equiv, 0.3 ml) and [4-(trifluoromethoxy)phenyl]phenyl]methanamine23B (1.1 equiv., 590 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. The residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (4:6 EtOAc:petroleumether) afforded 200 mg of a pale yellow solid. Yield=18.3% ¹HNMR (DMSO,200 MHz) δ 1.09 (3H, t, J=7 Hz), 3.44 (2H, q, J=7.2 Hz), 4.43 (2H, d,J=6 Hz), 5.40 (1H, s), 6.19 (1H, s), 7.33 (2H, m), 7.44 (3H, m), 7.60(3H, m), 7.75 (2H, dd, J=8.8 Hz, J′=2.2 Hz), 8.80 (1H, bt) [M⁺¹] 545.1(C₂₃H₂₀ClF₃N₂O₄S₂ requires 544.99).

Example 562-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide

Preparation of2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamideExample 56

A solution of acid 4A (260 mg, 1 mmol) in THF (25 mL) was added withDEPC (0.18 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv.,277.5 mg) was added. The reaction mixture was then stirred at roomtemperature overnight. The solvent was removed under reduced pressure,the residue was suspended in EtOAc (30 mL) and washed with water (50 mL)and brine. The separated organic phase, after anhydrification overNa₂SO₄, was evaporated under reduced pressure and the residue waspurified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford apale yellow solid (100 mg) after crystallization from a mixture ofdiethyl ether/petroleum ether. Yield=49%, ¹HNMR (DMSO, 400 MHz) δ 2.93(3H, s), 4.48 (d, 2H, J=6 Hz), 5.08 (s, 1H), 5.87 (s, 1H), 7.35 (d, 1H),7.37 (t, 2H, J=8.8 Hz), 7.82 (m, 4H), 8.03 (s, 1H), 8.28 (d, 2H, J=8.4Hz), 8.63 (d, 1H, J=5.2 Hz), 8.95 (bt, 1H); [M⁺¹] 494.47 (C₂₃H₁₉F₄N₃O₃Srequires 493.47).

Example 571-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide

Synthesis of methyl1-[methyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxylate 14A

A solution of 13A (1 g, 3.67 mmol) in DMF (15 mL) was added with an.K₂CO₃ (1.5 mol eq, 0.76 g) and, after few minutes, 2-iodomethane (1.2mol eq, 0.81 ml) was added and the mixture was heated at 50° C. for 12h. The solvent was removed under reduced pressure, water was added tothe residue (60 mL) and the aqueous phase was extracted with EtOAc (3×30mL). The recombined organic phases were dried over Na₂SO₄ and evaporatedunder reduced pressure to afford 14A as a pale yellow oil (950 mg, 90%yield). ¹HNMR (DMSO, 200 MHz) δ 2.43 (bs, 4H), 2.88 (s, 3H), 2.90 (s,3H), 7.42 (t, 2H, J=8.2), 7.87 (m, 2H).

Synthesis of1-[methyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxylic acid 15A

A solution of 14A (1.3 g, 4.52 mmol) in dioxane (40 mL) was added with10% NaOH aq. solution (20 mL) and the mixture was heated at 50° C.overnight. The organic solvent was removed under reduced pressure andthe aqueous phase was acidified with 10% HCl. The solid formed wascollected by filtration, washed with water (2×20 mL) and dried to afford15A as white solid (1.0 g, 81% yield). ¹HNMR (DMSO, 200 MHz) δ 1.40 (bs,4H), 2.91 (s, 3H), 7.42 (m, 2H), 7.80 (m, 2H), 12.60 (bs, 1H).

Preparation of1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 57

Acid 15A (350 mg, 1.28 mmol) was dissolved in 5 ml of THF and at rt DEPC(0.25 mL, 1.3 mol eq) and[3-[4-(trifluoromethoxy)phenyl]phenyl]methanamine 23B (0.376 g, 1.1 moleq) were added to the solution. The mixture was stirred at rt overnightthen evaporated. he residue was dissolved in AcOEt (30 ml) and washedwith water (1×20 ml) and brine. The organic phase was dried over sodiumsulfate and concentrated under vacuum. The purification of the crude bychromatographic column (3:7 EtOAc:Petroleum ether) afforded 100 mg of awhite solid. Yield=15% ¹HNMR (DMSO, 200 MHz) δ 1.09 (2H, bs), 1.34 (2H,bs), 3.00 (3H, s), 4.35 (2H, d, J=5.8 Hz), 7.43 (8H, m), 7.81 (4H, m),8.17 (1H, bt); [M⁺¹] 523.9 (C₂₅H₂₂F₄N₂O₄S requires 522.51).

Example 581-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide

Preparation of1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 58

Acid 15A (820 mg, 3 mmol) was dissolved in 5 ml of THF and at rt DEPC(1.1 equiv, 0.5 ml) and [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine23A (1.1 equiv., 835 mg) were added to the solution. The mixture wasstirred at rt overnight then evaporated. he residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:Petroleumether) afforded 250 mg of a white solid. Yield=16.5% ¹HNMR (DMSO, 400MHz) δ 1.09 (2H, bs), 1.32 (2H, bs), 2.99 (3H, s), 4.34 (2H, d, J=5.8Hz), 7.35 (4H, m), 7.58 (2H, m), 7.80 (4H, m), 7.87 (2H, d, J=8 Hz),8.18 (1H, bt); [M⁺¹] 507.9 (C₂₅H₂₂F₄N₂O₃S requires 506.51).

Example 591-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamideExample 59

A solution of acid 18 (0.50 g, 1.62 mmol) in THF (25 mL) was added withDEPC (0.32 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for 10′. [3-[4-(trifluoromethyl)phenyl]phenyl]methanamine23A (1.1 equiv., 450 mg) was added to the solution. The mixture wasstirred at rt overnight then evaporated. he residue was dissolved inAcOEt (30 ml) and washed with water (1×20 ml) and brine. The organicphase was dried over sodium sulfate and concentrated under vacuum. Thepurification of the crude by chromatographic column (3:7 EtOAc:Petroleumether) afforded 350 mg of a white solid. Yield=40% ¹HNMR (DMSO, 200 MHz)δ 1.19 (5H, m), 1.41 (2H, bs), 3.39 (2H, m), 4.38 (2H, d, J=5.8 Hz),7.23 (1H, dd, J=4 Hz), 7.33 (1H, d), 7.41 (1H, t), 7.50 (3H, m), 7.79(4H, dd, J=5.8 Hz), 8.11 (1H, bs); [M⁺¹] 544.9 (C₂₄H₂₂ClF₃N₂O₃S₂requires 543.02).

Example 601-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methyl]cyclopropanecarboxamide

Synthesis of 4-[4-(trifluoromethyl)phenyl]pyridine-2-carbonitrile 20C

4-Chloropyridine-2-carbonitrile 19B (2.0 gr, 14.44 mmol) was dissolvedin 35 ml of dioxane. The solution was added with cesium carbonate (6.8gr), [4-(trifluoromethyl)phenyl]boronic acid (1.2 equiv., 3.3 gr) andpalladium acetate/XPhos (80 mg/280 mg) under argon atmosphere. Themixture was stirred at 100° C. for 4 hours. The reaction is filteredthrough a pad of celite, concentrated and crystallized from diethylether/petroleum ether to give a beige solid (3.2 gr, 12.85 mmol, yield:89%) ¹HNMR (DMSO, 400 MHz) δ 7.92 (2H, dd, J=8.0 Hz), 8.12 (3H, m), 8.51(1H, dd), 8.39 (1H, dd, J=5.2 Hz)

Synthesis of [4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methanamine 21C

The nitrile 20C (3.2 g, 12.85 mmol) dissolved in 50 ml of diethyl etherwas added dropwise to a mixture of LiAlH₄ (912 mg, 2 equiv.) in diethylether (80 mL) and stirred at 0° C. Then, the mixture was stirred at roomtemperature overnight. The excess of LiAlH₄ was destroyed by wateraddition at 0° C., the solid formed was filtered, washed with Et₂O andthe filtrate was dried over Na₂SO₄ and evaporated to dryness to obtain2.5 g of the amine as a yellow oil. The amine was used for the followingstep without purification.

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methyl]cyclopropanecarboxamideExample 60

A solution of acid 15B (0.5 g, 1.7 mmol) in THF (30 mL) was added withDEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methanamine 21C (0.51 g, 1.18mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, the residue was suspended in EtOAc (40mL) and washed with water (50 mL) and brine. The separated organic phasewas dried over Na₂SO₄ and evaporated under reduced pressure and theresidue was purified by flash chromatography (3:7 EtOAc:Petroleum ether)to afford a white solid (0.18 g) after crystallization from diethylether. Yield=20%, ¹HNMR (DMSO, 200 MHz) δ 1.11 (bs, 2H), 1.23 (t, 3H,J=8), 1.26 (bs, 2H), 3.41 (bs, 2H), 4.49 (d, 2H); 7.44 (m, 2H), 7.66(dd, 1H), 7.74 (bs, 1H), 7.90 (m, 4H), 8.02 (d, 2H, J=8), 8.26 (bt, 3H),8.63 (dd, 1H, J=5.2). [M⁺¹] 522.53 (C₂₅H₂₃F₄N₃O₃S requires 521.53).

Example 611-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 61

A solution of acid 15B (0.5 g, 1.7 mmol) in THF (30 mL) was added withDEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[4-[4-(trifluoromethoxy)phenyl]-2-pyridyl]methanamine 27C (0.61 g, 1.07mol eq) and a catalytic amount of TEA were added, then the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure, the residue was suspended in EtOAc (40mL) and washed with water (50 mL) and brine. The separated organic phasewas dried over Na₂SO₄ and evaporated under reduced pressure and theresidue was purified by flash chromatography (3:7 EtOAc:Petroleum ether)to afford a white solid (0.18 g) after crystallization from diethylether. Yield=17%, ¹HNMR (DMSO, 200 MHz) δ 1.13 (bs, 2H), 1.20 (t, 3H,J=8), 1.25 (bs, 2H), 3.46 (bq, 2H), 4.29 (d, 2H); 6.44 (s, 1H), 7.12 (s,1H), 7.42 (m, 4H), 7.96 (m, 2H), 8.13 (m, 3H). [M⁺¹] 607.53(C₂₉H₃₀F₄N₄O₄S requires 606.63).

Example 621-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 62

with solution of acid 15B (0.5 g, 1.7 mmol) in THF (30 mL) was addedwith DEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27D(0.50 g, 1.04 mol eq) and a catalytic amount of TEA were added, then thereaction mixture was stirred at room temperature overnight. The solventwas removed under reduced pressure, the residue was suspended in EtOAc(40 mL) and washed with water (50 mL) and brine. The separated organicphase was dried over Na₂SO₄ and evaporated under reduced pressure andthe residue was purified by flash chromatography (1:1 EtOAc:Petroleumether) to afford a white solid (220 mg) after crystallization fromdiethyl ether. Yield=21%, ¹HNMR (DMSO, 200 MHz) δ 1.10 (bs, 2H), 1.20(t, 3H, J=8), 1.35 (bs, 2H), 3.46 (bq, 2H), 3.55 (bt, 4H), 3.74 (bt,4H), 4.34 (d, 2H); 6.81 (s, 1H), 7.39 (m, 3H), 7.86 (m, 4H), 8.23 (bm,3H). [M⁺¹] 607.81 (C₂₉H₃₀F₄N₄O₄S requires 606.63).

Example 63N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide

Synthesis of2-chloro-6-[4-(cyclopropylmethyl)piperazin-1-yl]pyridine-4-carbonitrile25D

A solution of 24 (2.5 g, 14.46 mmol) in abs. EtOH (10 mL) was added withTEA (2 ml) and 4-cyclopropylmethylpiperazine (1.36 mL, 1 mol eq) and themixture was heated at 50° C. overnight. The solvent was removed underreduced pressure, water was added to the residue and the aqueous phasewas extracted with EtOAc (3×40 mL). The recombined organic phase waswashed with brine (1×60 mL), dried over Na₂SO₄ and evaporated to afford25D as a pale yellow solid (2.4 g, 8.67 mmol, 60% Yield). ¹HNMR (DMSO,400 MHz) δ 0.08 (m, 2H), 0.46 (m, 2H), 0.84 (m, 1H), 2.20 (d, 2H, J=6.8Hz), 2.50 (m, 4H), 3.56 (m, 4H), 7.06 (s, 1H), 7.32 (s, 1H).

Synthesis of2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]pyridine-4-carbonitrile26F

The nitrile 25D (2.4 g, 8.67 mmol), 4-trifluoromethoxyphenylboronic acid(2.15 g, 1.1 mol eq), palladium acetate (45 mg), cesium carbonate (4.5g, 2 mol eq), and XPhos (190 mg) were mixed, placed under a nitrogenatmosphere and dioxane (10 mL) was added. The mixture was heated at 100°C. overnight. After cooling, the mixture was filtered through a celitepad, washed with dioxane (2×20 mL) and concentrated under reducedpressure. The residue was used for the next step without furtherpurification.

Synthesis of[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine27F

A solution of nitrile 26F (2.5 g, 6.2 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.67 g) in diethyl ether(30 mL) stirred at 0° C. After the addition was completed, the mixturewas stirred at room temperature overnight. The excess of LiAlH₄ wasdestroyed at 0° C. by addition of small amount of water (30 mL), thesolid formed was filtered off and the organic filtrate was separated,washed with brine (50 mL) and dried over Na₂SO₄. The organic phase wasevaporated under reduced pressure to afford 27G as a pale yellow oil(2.0 g, 80% yield). ¹HNMR (DMSO, 200 MHz) δ 0.08 (m, 2H), 0.47 (m, 2H),0.77 (m, 1H), 2.14 (d, 2H, J=6.6), 2.44 (m, 4H), 2.86 (bs, 2H), 3.45 (m,4H), 3.65 (s, 2H), 6.86 (s, 1H), 7.18 (s, 1H), 7.88 (d, 2H, J=7.8), 8.24(d, 2H, J=8.2).

Preparation ofN-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamideExample 63

A solution of acid 4B (273.28 mg, 1 mmol) in THF (10 mL) was added withDEPC (0.15 mL, 1.1 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine27F (405 mg, 1.04 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (40 mL) and washed with water (50 mL) and brine. The separatedorganic phase was dried over Na₂SO₄ and evaporated under reducedpressure and the residue was purified by flash chromatography (9:1EtOAc:methanol) to afford a white solid (200 mg) after crystallizationfrom diethyl ether. Yield=30%, ¹HNMR (DMSO, 200 MHz) δ 0.05 (m, 2H),0.45 (bm, 2H), 0.82 (m, 1H), 1.08 (t, 3H), 2.17 (d, 2H, J=6.4), 3.34(bm, 4H), 3.49 (bm, 4H), 4.43 (d, 2H, J=6.2), 5.13 (s, 1H); 6.09 (s,1H), 6.80 (s, 1H), 7.30 (s, 1H), 7.47 (m, 4H), 7.85 (m, 4H), 8.74 (t,1H). [M⁺¹] 662.90 (C₃₂H₃₅F₄N₅O₄S requires 661.71).

Example 64N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide

Synthesis of2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile26G

The nitrile 25D (2.4 g, 8.67 mmol), 4-trifluoromethylphenylboronic acid(2.05 g, 1.1 mol eq), palladium acetate (45 mg), cesium carbonate (4.5g, 2 mol eq), and XPhos (190 mg) were mixed, placed under a nitrogenatmosphere and dioxane (10 mL) was added. The mixture was heated at 100°C. overnight. After cooling, the mixture was filtered through a celitepad, washed with dioxane (2×20 mL) and concentrated under reducedpressure. The residue was used for the next step without furtherpurification.

Synthesis of[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27G

A solution of nitrile 26G (2.5 g, 6.7 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (0.67 g) in diethyl ether(30 mL) stirred at 0° C. After the addition was completed, the mixturewas stirred at room temperature overnight. The excess of LiAlH₄ wasdestroyed at 0° C. by addition of small amount of water (30 mL), thesolid formed was filtered off and the organic filtrate was separated,washed with brine (50 mL) and dried over Na₂SO₄. The organic phase wasevaporated under reduced pressure to afford 27G as a pale yellow oil(2.0 g, 80% yield). ¹HNMR (DMSO, 200 MHz) δ 0.00 (m, 2H), 0.37 (m, 2H),0.77 (m, 1H), 2.14 (d, 2H, J=6.6), 2.44 (m, 4H), 2.80 (bs, 2H), 3.50 (m,4H), 3.61 (s, 2H), 6.76 (s, 1H), 7.23 (s, 1H), 7.68 (d, 2H, J=8), 8.14(d, 2H, J=8).

Preparation ofN-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamideExample 64

A solution of acid 15B (0.5 g, 1.7 mmol) in THF (30 mL) was added withDEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27G (636 mg, 1.04 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (40 mL) and washed with water (50 mL) and brine. The separatedorganic phase was dried over Na₂SO₄ and evaporated under reducedpressure and the residue was purified by flash chromatography (9:1EtOAc:methanol) to afford a white solid (340 mg) after crystallizationfrom diethyl ether. Yield=30%, ¹HNMR (DMSO, 200 MHz) δ 0.40 (m, 2H),0.63 (bm, 2H), 0.86 (m, 1H), 1.08 (m, 2H), 1.23 (t, 3H), 1.30 (bm, 2H),3.06 (bm, 4H), 3.39 (bm, 4H), 3.64 (bm, 2H), 4.44 (m, 4H); 6.92 (s, 1H),7.44 (m, 3H), 7.86 (m, 4H), 8.26 (bm, 3H). [M⁺¹] 660.81 (C₃₃H₃₇F₄N₅O₃Srequires 659.74).

Example 651-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 65

A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added withDEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27G (560 mg, 1.04 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (40 mL) and washed with water (50 mL) and brine. The separatedorganic phase was dried over Na₂SO₄ and evaporated under reducedpressure and the residue was purified by flash chromatography (9:1EtOAc:methanol) to afford a white solid (220 mg) after crystallizationfrom diethyl ether. Yield=21.5%, ¹HNMR (DMSO, 200 MHz) δ 0.40 (m, 2H),0.65 (bm, 2H), 0.94 (m, 1H), 1.12 (m, 2H), 1.28 (t, 3H), 1.40 (bm, 2H),3.04 (bm, 4H), 3.39 (bm, 4H), 3.43 (bm, 2H), 3.44 (m, 4H); 4.40 (bm,4H), 6.87 (s, 1H), 7.30 (m, 2H), 7.60 (d, 1H, J=3.2), 7.82 (d, 2H,J=8.2), 8.25 (bm, 3H). [M⁺¹] 682.98 (C₃₁H₃₅ClF₃N₅O₃S₂ requires 682.22).

Example 66N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide

Synthesis of2-chloro-6-[4-(cyclohexyl)piperazin-1-yl]pyridine-4-carbonitrile 25E

A solution of 24 (2.5 g, 14.46 mmol) in abs. EtOH (10 mL) was added withTEA (2 ml) and N-cyclohexylpiperazine (2.43 g, 1 mol eq) and the mixturewas heated at 70° C. for 4 hours. The solvent was removed under reducedpressure, water was added to the residue and the aqueous phase wasextracted with EtOAc (3×40 mL). The recombined organic phase was washedwith brine (1×60 mL), dried over Na₂SO₄ and evaporated to afford 25E asa pale yellow solid (2.2 g, 7.2 mmol, 49% Yield). ¹HNMR (DMSO, 200 MHz)δ 1.18 (bm, 4H), 1.59 (bm, 1H), 1.74 (bm, 4H), 2.26 (bm, 2H), 2.53 (m,4H), 3.52 (m, 4H), 7.04 (s, 1H), 7.30 (s, 1H).

Synthesis of2-[4-(cyclohexyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]pyridine-4-carbonitrile26E

The nitrile 25E (2.2 g, 7.2 mmol), 4-trifluoromethylphenylboronic acid(2.05 g, 1.1 mol eq), palladium acetate (45 mg), cesium carbonate (4.5g, 2 mol eq), and XPhos (190 mg) were mixed, placed under a nitrogenatmosphere and dioxane (10 mL) was added. The mixture was heated at 100°C. overnight. After cooling, the mixture was filtered through a celitepad, washed with dioxane (2×20 mL) and concentrated under reducedpressure. The residue was a yellow oil. ¹HNMR (DMSO, 200 MHz) δ 1.14(bm, 4H), 1.59 (bm, 1H), 1.75 (bm, 4H), 2.26 (bm, 2H), 2.58 (m, 4H),3.62 (m, 4H), 7.33 (s, 1H), 7.66 (s, 1H), 7.82 (d, 2H, J=8.2), 8.28 (d,2H, J=8.2).

Synthesis of[2-[4-(cyclohexyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E

A solution of nitrile 26E (3.2 g, 7.7 mmol) in diethyl ether (30 mL) wasadded in small amounts to a mixture of LiAlH₄ (800 mg) in diethyl ether(30 mL) stirred at 0° C. After the addition was completed, the mixturewas stirred at room temperature overnight. The excess of LiAlH₄ wasdestroyed at 0° C. by addition of small amount of water (30 mL), thesolid formed was filtered off and the organic filtrate was separated,washed with brine (50 mL) and dried over Na₂SO₄. The organic phase wasevaporated under reduced pressure to afford 27E as a pale yellow oil(1.76 g, 55% yield). ¹HNMR (DMSO, 200 MHz) δ 1.14 (bm, 4H), 1.52 (bm,1H), 1.77 (bm, 4H), 2.26 (bm, 2H), 2.60 (m, 4H), 3.36 (b, 2H), 3.55 (m,4H), 3.70 (s, 2H), 6.84 (s, 1H), 7.32 (s, 1H), 7.79 (d, 2H, J=8.2), 8.24(d, 2H, J=8.2).

Preparation ofN-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamideExample 66

A solution of acid 15B (0.5 g, 1.7 mmol) in THF (30 mL) was added withDEPC (0.34 mL, 1.3 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(cyclohexyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E (712 mg, 1.04 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (40 mL) and washed with water (50 mL) and brine. The separatedorganic phase was dried over Na₂SO₄ and evaporated under reducedpressure and the residue was purified by flash chromatography (9:1EtOAc:methanol) to afford a white solid (140 mg) after crystallizationfrom diethyl ether. Yield=20%, ¹HNMR (DMSO, 200 MHz) δ 1.18 (bm, 9H),1.83 (bm, 4H), 2.30 (bm, 1H), 2.59 (bm, 4H), 3.34 (bm, 2H), 3.57 (bm,4H), 4.40 (bd, 2H), 6.82 (s, 1H), 7.34 (m, 3H), 7.83 (m, 4H), 8.21 (bm,3H). [M⁺¹] 688.41 (C₃₅H₄₁F₄N₅O₃S requires 687.79).

Example 671-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide

Preparation of1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamideExample 67

A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added withDEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at roomtemperature for about 5 minutes. Then[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine27E (628 mg, 1.04 mol eq) and a catalytic amount of TEA were added, thenthe reaction mixture was stirred at room temperature overnight. Thesolvent was removed under reduced pressure, the residue was suspended inEtOAc (40 mL) and washed with water (50 mL) and brine. The separatedorganic phase was dried over Na₂SO₄ and evaporated under reducedpressure and the residue was purified by flash chromatography (9:1EtOAc:methanol) to afford a white solid (110 mg) after crystallizationfrom diethyl ether. Yield=10%, ¹HNMR (DMSO, 200 MHz) δ 1.15 (bm, 9H),1.80 (bm, 4H), 2.35 (bm, 1H), 2.59 (bm, 4H), 3.37 (bm, 2H), 3.65 (bm,4H), 4.45 (bd, 2H), 6.89 (s, 1H), 7.35 (m, 2H), 7.60 (d, 1H, J=3.4),7.82 (d, 2H, J=8), 8.25 (bm, 3H). [M⁺¹] 711.65 (C₃₃H₃₉ClF₃N₅O₃S₂requires 710.27).

Substituents:

A, X=4-F and R=methyl; B, X=4-F and R=ethyl; C, X=4-Cl and R=methyl; D,X=4-Cl and R=ethyl; E, X=4-CH₃ and R=methyl; F, X=3-F and R=ethyl; G,X=3,4-difluoro and R=ethyl.

5-7H, Z=H; 5-7I, Z=Cl. For 2A, 2C and 2E, R=H.

Substituents:

A, X=F and R=methyl; B, X=F and R=ethyl; C, X=Cl and R=methyl; D, X=Cland R=ethyl. For 9A and 9C, R=H.

Substituents:

A, X=F and R=methyl; B, X=F and R=ethyl, C, X=Cl and R=ethyl. For 15D,X=F.

Substituents:

19A, Y′=N, Y²=CH; 19B, Y′=CH, Y²=N; 20-21A, Y′=N, Y²=CH, X=—CF₃; 20-21B,Y′=N, Y²=CH, X=—OCF₃; 20-21C=Y′=CH, Y²=N, X=—CF₃; 23A, X=CF₃; 23B,X=—OCF₃

Substituents:

25A, R=pyrrolidine; 25B, R=morpholine; 25C, R=N,N′-dimethylamino; 25D,R=N-cyclopropylmethyl-piperazine; 25E, R=N-cycloexylpiperazine; 25F,R=methoxy; 25G, R=ethoxy; 25H, R=isopropyloxy; 26-27A, R=pyrrolidine andX=—CF₃; 26-27B, R=morpholine and X=—CF₃; 26-27C, R=pyrrolidine andX=—OCF₃; 26-27D, R=morpholine and R=—OCF₃; 26-27E, R=N,N′-dimethylaminoand X=—CF₃; 26-27F, R=N-cyclopropylmethyl-piperazine and X=—OCF₃;26-27G, R=N-cyclopropylmethyl-piperazine and X=—CF₃; 26-27H, R=N—cycloexylpiperazine and R=—CF₃; 26-27I, R=—OCH₃ and X=—CF₃; 26-27L,R=—OCH₂CH₃ and X=—CF₃; 26-27M, R=Isopropyloxy and X=—CF₃; 28-29A,X=—CF₃; 28-29B, X=—OCF₃.

Pharmacology

Drugs and reagents were obtained from the indicated companies:PF-4840154, ionomycin, laminin, poly-L-lysine, collagenase, trypsin,L-glutamine, penicillin/streptomycin, DMEM, HBSS, mouse-NGF-7S, ARA-C,HEPES, Tween80, Complete Freund's Adjuvant (CFA) and BSA (Sigma, Italy);FBS and HS (Gibco, Italy); Fura-2-AM-ester (Vinci-Biochem, Italy) andMethylcellulose (Fluka, Switzerland). The stock concentration (10 mM) ofPF-4840154, Fura-2-AM-ester, ionomycin and all tested compounds wereprepared in 100% DMSO.

PF-4840154 (1 μM)-Induced Ca²⁺ Fluorescence Measurements in A549 CellLine

Human lung adenocarcinoma epithelial cell line (A549) stably expressingnative human TRPA1 receptors were used. The cells were cultured inmedium consisting of Eagle's minimal essential medium (EMEM)supplemented with 10% fetal bovine serum (FBS), penicillin (100 IU/ml),streptomycin (100 mg/ml), L-glutamine (2 mM), sodium bicarbonate (2.5g/L) and HEPES (24 mM). Cells were kept at 37° C. in 5% CO₂/humidifiedair. For the experiments the cells were seeded at a density of 16,000cells/well into 96-well black, clear-bottom plates. After 24 hoursincubation the cells were loaded with medium supplemented with 2.5 mMprobenecid, 3 μM of the calcium sensitive fluorescent dye Fluo-4 AM and0.01% pluronic acid, for 30 min at 37° C. Afterwards the loadingsolution was aspirated and 100 μ/well of assay buffer: Hank's BalancedSalt Solution (HBSS) supplemented with 2.5 mM probenecid and 500 μMBrilliant Black (Aldrich) was added. Stock solutions (100 mM) of ligandswere made in Dimethyl Sulfoxide (DMSO) and stored at −20° C. Serialdilutions of ligands for experimental use were made in HBSS buffer.After placing both plates (cell culture and compound plate) into theFlexStation II (Molecular Device, Union City, Calif. 94587, US),fluorescence changes were measured. On-line additions were carried outin a volume of 50 μwell. To facilitate drug diffusion into the wells inantagonist type experiments, the studies were performed at 36.5° C. andthree cycles of mixing (25 μl from each well moved up and down 3 times)were performed immediately after antagonist injection to the wells. Allexemplified compounds were tested alone (to address residual agonisticactivity) and against 1 μM of PF-4840154 to address inhibitory activityat the initial concentration of 10 μM. For selected examples the entireinhibitory concentration-response curves were constructed and the IC₅₀value calculated.

PF-4840154 (10 μM)-Induced Ca²⁺ Fluorescence Measurements in CulturedRat Dorsal Root Ganglia Neurons

Male SD rats (˜50 g, Charles River, Italy) were terminally anaesthetizedand decapitated. Dorsal root ganglia were removed and placed in coldHank's balanced salt solution (HBSS) before being transferred tocollagenase (2 mg/ml) and trypsin (1 mg/ml) for 35 min at 37° C. Theganglia, placed in cold DMEM supplemented with 10% fetal bovine serum,10% horse serum, 2 mM L-glutamine, 100 U/ml penicillin and 100 μg/mlstreptomycin, were dissociated in single cells by several passagesthrough a series of syringe needles (23G down to 25G). The medium andthe ganglia were filtered to remove debris, topped up with 4 ml of DMEMmedium and centrifuged (1100 rpm for 6 min). The final cell pellet wasre-suspended in DMEM medium [supplemented with 100 ng/ml mouse NerveGrowth Factor (mouse-NGF-7S) and cytosine-β-D-arabinofuranoside freebase (ARA-C) 2.5 μM]. The cells were plated on poly-L-lysine (8.3 μM)-and laminin (5 μM)-coated 25 mm glass cover slips and kept for 2 days at37° C. in a humidified incubator gassed with 5% CO₂ and air, thentreated with Fura-2-AM-ester (5 μM) in a Ca²⁺ buffer solution having thefollowing composition (mM): CaCl₂ 1.4, KCl 5.4, MgSO₄ 0.4, NaCl 135,D-glucose 5, HEPES 10 with BSA (0.1%), at pH 7.4, for 40 min at 37° C.The cells were then washed twice with the Ca²⁺ buffer solution andtransferred to a chamber on the stage of a Nikon eclipse TE300microscope. Fura-2-AM-ester was excited at 340 nM and 380 nM to indicaterelative [Ca²⁺]_(i) changes by the F₃₄₀/F₃₈₀ ratio recorded with adynamic image analysis system (Laboratory Automation 2.0, RCS, Florence,Italy) and the cells were allowed (at least 10 min) to attain a stablefluorescence before beginning the experiment. A calibration curve wasset up using buffer containing Fura-2-AM-ester and determinantconcentrations of free Ca²⁺. This curve was then used to convert thedata obtained from the F₃₄₀/F₃₈₀ ratio to [Ca²⁺]_(i) (nM).

All exemplified compounds were tested at the concentration of 10 μMagainst the calcium uptake induced by 10 μM PF-4840154. For selectedexamples, the entire concentration response curves were constructed andthe respective IC₅₀ value calculated.

Agonist (PF-4840154)-Induced Mechanical Hyperalgesia in Rats

The method is used to investigate the anti-hyperalgesic effects of thecompounds listed in the present invention following agonist(PF-4840154)-induced hyperalgesic responses. The activity is indicativeof TRPA1 receptor occupancy following oral dosing. Specifically, male SDrats (Charles River, Italy) weighing 70-100 g. were used. Theanti-hyperalgesic effects were investigated using the electronicdynamometer test. PF-4840154 (Sigma, USA) was used to induce mechanicalhyperalgesia. Local, intraplantar injection of PF-4840154 at 0.05nmol/50 μl/paw caused the reduction of the hind paw withdrawal responseinduced by mechanical stimuli. Mechanical stimulation was induced inbasal condition and 30, 60, 120, 180 and 240 minutes after the oraladministration of the antagonists dissolved in 2.5% DMSO and 30%Solutol. Compounds were orally administered (30 μmol/kg/10 ml) to rats 1hour before the injection of PF-4840154 into the plantar surface of arat's hind using a micro syringe.

Oxaliplatin-Induced Mechanical Hyperalgesia in Rats

The method described by Nassini et al. (Pain, 2011, 152(7), 1621-31) wasused with minor modifications. Restrained rats were treated with asingle intravenous bolus injection of oxaliplatin (2.5 mg/kg) dissolvedin normal saline. This approach was sufficient to elicit reproducibleallodynic behaviour evident 3 days post injection and during the daythereafter. For convenience all acute experiments were conducted 7 dayspost injection when compounds were orally administered at 30 μmol/kg.

Results

PF-4840154 (1 μM)-Induced Ca²⁺ Fluorescence Measurements in CulturedA549 Cell Line

PF-4840154 (1 μM) increased [Ca²⁺] in the vast majority (95%) ofcultured cells which were thereby identified as TRPA1 expressing cells.All synthesized derivatives were initially tested at the finalconcentration of 10 μM and then, most active compounds were furtherinvestigated to determine their respective potency evaluating the IC₅₀value defined as the concentration eliciting 50% inhibition under theexperimental condition used. The compounds were able to effectivelyinhibit calcium uptake and several exhibited an inhibitory activity atthe tested concentration comprised between 80% and 100% of agonistresponse. Several derivatives among those of Examples 1-67 showed 1050values <50 nM.

The IC₅₀ values of the compounds of Examples 1, 7, 10, 11, 12, 14, 15,34, 37, 38, 39, 40, 43, 44, 50, 51, 53, 55 and 59 calculated againstPF-4840154-evoked [Ca²⁺]_(i) mobilization were 15, 36, 25, 17, 33, 40,22, 25, 18, 17, 20, 16, 48, 18, 19, 41, 17, 31, 38 nM, respectively.

Tables 1, describes the calcium assay data obtained in A549 cells forexemplified compounds of Formula I.

TABLE 1 Example % inhibition at 10 μM IC₅₀ (nM) 1 100% 15 2  98% 135 3 95% 93 4  98% 78 5  99% 100 6 100% 355 7 100% 36 8 100% 76 9  98% 68 10 99% 25 11  99% 17 12 100% 33 13  99% 182 14 100% 40 15 100% 22 16  99%457 17  98% 120 18 100% 93 19 100% 74 20  96% 251 21 100% 323 22  97%246 23  98% 437 24  97% 724 25 100% 76 26 100% 151 27 100% 135 28 100%129 29 100% 138 30 100% 100 31 100% 57 32  80% >4 μM 33  55% >2 μM 34100% 25 35 100% 58 36 100% 118 37 100% 18 38 100% 17 39 100% 20 40 100%16 41  96% 135 42 100% 104 43 100% 48 44 100% 18 45 100% 151 46  97% 6347  96% 113 48  96% 260 49  98% 95 50 100% 19 51 100% 41 52  99% 87 53100% 17 54  47% >10 μM 55 100% 31 56 100% 275 57  97% 275 58 100% 160 59 99% 38 60 100% 423 61  95% 784 62 100% 660 63  99% 175 64  99% 338 65100% 327 66  93%  1.5 μM 67  95% 590

PF-4840154 (10 μM)-Induced Ca²⁺ Fluorescence Measurements in CulturedPrimary Dorsal Root Rat Neurons

As mentioned above, selected compounds were also characterized withrespect to their specific activity on PF-4840154-induced [Ca²⁺]_(i)mobilization in primary culture of rat dorsal ganglia neurons. In thisassay, Examples 1, 7, 10, 11, 14, 15, 19 and 38 had estimated IC₅₀ of14, 29, 47 20, 60, 32, 68 nM, and 14 respectively.

Tables 2 below, describes the calcium assay data obtained in primaryculture of rat dorsal ganglia neurons of selected compounds of formulaI.

TABLE 2 Example IC50 (nM) 1 14 7 29 10 47 11 20 14 60 15 32 19 68 38 14

Agonist (PF-4840154)-Induced Mechanical Hyperalgesia in Rats

The more potent antagonists were orally administered at 30 μmol/kg torats and their anti-hyperalgesic activity tested against PF-4840154administered intraplantary at the dose of 0.05 nmol/50 μl/paw. Examples1, 4, 5, 7, 10, 11, 14, 15, 19, 26, 30, 37, 38, 50, 51, 53 and 59 wereable to effectively counteract PF-4840154 producing a robust andlong-lasting reversal of mechanical allodynia showing 80, 67, 76, 74,63, 72, 75, 72, 74, 64, 82, 95, 87, 76, 76, 89 and 111% of reversal,respectively.

Tables 3 below, describes the anti-hyperalgesic activity of selectedexamples of Formula I in PF-4840154-induced hyperalgesic responses.

TABLE 3 Example Maximal inhibition (%) 1 80 4 67 5 76 7 74 10 63 11 7214 75 15 72 19 74 26 64 30 82 37 95 38 87 50 76 51 76 53 89 59 111

Oxaliplatin-Induced Mechanical Hyperalgesia in Rats

The more potent antagonists were orally administered at 30 μmol/kg torats 7 days post intravenous injection of oxaliplatin at the dose of 2.5mg/kg and their anti-nociceptive effect was measured. Examples 1, 34,37, 40, 50, 51, 53 and 59 were able to effectively counteract theoxaliplatin effect producing a robust and long-lasting reversal ofmechanical allodynia showing 97, 71, 82, 103, 82, 65, 83 and 67% ofreversal, respectively.

Tables 4 below, describes the anti-hyperalgesic activity of selectedexamples of Formula I in oxaliplatin-induced mechanical hyperalgesia.

TABLE 4 Example Maximal inhibition (%) 1 97 34 71 37 82 40 103 50 82 5165 53 83 59 67

1. A compound of formula (I)

wherein: Ar₁ is: i) phenyl substituted with 0, 1, 2 or 3 substituentsR_(a); or ii) a 5- or 6-membered monocyclic aromatic heterocycle ringoptionally substituted with one or two substituents R_(a); where eachR_(a) is independently halo, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CN, —CF₃, —OCF₃,—NO₂, —C(O)C₁₋₄alkyl or —CO₂H; Ar₂ is: i) phenyl substituted with 0, 1,2 or 3 substituents R_(b); where each R_(b) is independently halo,C₁₋₄alkyl, —C(O)NR_(c)R_(d), —OC₁₋₄alkyl, —OC₀₋₄alkylCF₃, —CN, —CF₃,—OCF₂H, —NO₂, —NR_(c)R_(d), —S(O)₀₋₂C₁₋₄alkyl, —C(O)C₁₋₄alkyl,S(O)(O)NH₂, —(CH₂)₀₋₂-morpholinyl, piperidin-1-yl, piperazinyl, saidpiperazinyl being optionally substituted with a methyl, or two R_(b)substituents on adjacent carbon atoms taken together form —O(CH₂)₁₋₂O—;ii) pyridyl substituted with 0, 1 or 2 substituents R_(e); where eachR_(e) is independently selected from halo, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CF₃, —NR_(c)R_(d) or 4-morpholinyl; or iii) a bicyclic 9-11-memberedaromatic heterocycle, optionally substituted with 1 substituent R_(f-)where R_(f) is —C₁₋₄alkyl; R_(c) and R_(d) are each independentlyselected from H or —C₁₋₄alkyl; R₁ is H, C₁₋₄alkyl-O—C₁₋₄alkyl, orC₁₋₄alkyl optionally substituted with halo; R₂, R₃, R₄, and R₅ are eachindependently H, halo or —C₁₋₄alkyl; n is 0 or 1 providing that when nis 1 the bond between C₁ and C₂ is single and when n is 0 the bondbetween C₁ and C₂ is double; each Y₁, Y₂ and Y3 is independently CH orN; R₆ is i) H, —C₁₋₄alkyl, —CF₃, —OR_(Z) or —NR_(h)Ri; where R_(h) isselected from: a) H, —C₀₋₄alkylCF₃, —C₁₋₄alkyl-N(CH₃)₂, saturatedC₃₋₇cycloalkyl or —C₁₋₄alkyl-monocyclic heteroaryl ring; b) —C₁₋₅alkyloptionally substituted with OH; c) —C₁₋₄alkyl-heterocycloalkyl, whereinsaid heterocycloalkyl is optionally substituted with —C₁₋₄alkyl; or d)—C₀₋₄alkyl-phenyl, said phenyl being optionally substituted with one ortwo R_(j) moieties; where each R_(j) is independently halo, —OC₁₋₄alkyl,Rz is —C₁₋₄alkyl, —C₁₋₄alkylCF₃ or —C₁₋₄alkyl-heterocycloalkyl; ii)1-pyrrolidinyl optionally substituted with a moiety selected from thegroup consisting of —NR_(k)R_(i) and —C₁₋₄alkyl, said —C₁₋₄alkyloptionally substituted with —OH; iii) 1-piperidinyl optionallysubstituted with —C₁₋₄alkyl, —C(O)NH₂, —CO₂C₁₋₄alkyl or—C₀₋₄alkyl-phenyl; iv) piperazinyl optionally substituted with—C₁₋₅alkyl, —OC₁₋₄alkyl, —C₀₋₄alkylpyridyl,—C₀₋₄alkyl-1-methyl-piperidin-4-yl, —C₀₋₄alkylNR_(k)R_(i) or—C₀₋₄alkyl-phenyl, said phenyl being optionally substituted with one ortwo R_(T) substituents; where each R_(T) substituent is selected fromthe group consisting of halo, —OCF₃, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CO₂C₁₋₄alkyl, —C(O) C₁₋₄alkyl and —C₀₋₄alkylNR_(k)R_(i) or two R_(T)substituents on adjacent carbon atoms taken together form —O(CH₂)₁₋₂O—;v) phenyl optionally substituted with halo, —CF₃, —OCF₃; vi) pyridyl;vii) morpholin-yl; R_(k) is H, —C₁₋₄alkyl or —C(O)₁₋₂C₁₋₄alkyl; R_(i) isH or C₁₋₄alkyl; N-oxides, isomers, enantiomers, racemic mixtures andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1 of formula (IA)

wherein: Ar₁ is: i) phenyl substituted with 0, 1, 2 or 3 substituentsR_(a); or ii) a 5-6-membered monocyclic aromatic heterocycle ring,optionally substituted with one or two substituents R_(a); where eachR_(a) is independently halo, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CN, —CF₃, —OCF₃,—NO₂, —C(O)C₁₋₄alkyl or —CO₂H; Ar₂ is: i) phenyl substituted with 0, 1,2 or 3 substituents R_(b); where each R_(b) is independently halo,C₁₋₄alkyl, —C(O)NR_(c)R_(d), —OC₁₋₄alkyl, —OC₁₋₄alkylCF₃, —CN, —CF₃,—OCF₂H, —NO₂, —NR_(c)R_(d), —S(O)₀₋₂C₁₋₄ alkyl, —C(O)C₁₋₄alkyl,S(O)(O)NH₂, —(CH₂)₀₋₂-morpholinyl, piperidin-1-yl, piperazinyl, saidpiperazinyl being optionally substituted with a methyl, or two R_(b)substituents on adjacent carbon atoms taken together form —O(CH₂)₁₋₂O—;ii) pyridyl substituted with 0, 1 or 2 substituents R_(e); where eachR_(e) is independently selected from halo, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CF₃, —NR_(c)R_(d) or 4-morpholinyl; or iii) a bicyclic 9-11-memberedaromatic heterocycle optionally substituted with 1 substituent R_(f′);where R_(f) is —C₁₋₄alkyl; R_(c) and R_(d) are each independentlyselected from H or —C₁₋₄alkyl; R₁ is H, C₁₋₄alkyl-O—C₁₋₄alkyl, orC₁₋₄alkyl optionally substituted with halo; R₂ and R₃ and are eachindependently H, halo or —C₁₋₄alkyl; each Y₁, Y₂ and Y₃ is independentlyCH or N; R₆ is i) H, —C₁₋₄alkyl, —CF₃, —OR_(z) or —NR_(h)R_(i); whereR_(h) is selected from: a) H, —C₀₋₄alkylCF₃, —C₁₋₄alkyl-N(CH₃)₂,saturated C₃₋₇cycloalkyl or —C₁₋₄alkyl-monocyclic heteroaryl ring; b)—C₁₋₅alkyl optionally substituted with OH; c)—C₁₋₄alkyl-heterocycloalkyl, wherein said heterocycloalkyl is optionallysubstituted with —C₁₋₄alkyl; or d) —C₀₋₄alkyl-phenyl, said phenyl beingoptionally substituted with one or two R_(j) moieties; where each R_(j)is independently halo, —OC₁₋₄alkyl, Rz is —C₁₋₄alkyl, —C₁₋₄alkylCF₃ or—C₁₋₄alkyl-heterocycloalkyl; ii) 1-pyrrolidinyl optionally substitutedwith a moiety selected from the group consisting of —NR_(k)R_(i) and—C₁₋₄alkyl, said —C₁₋₄alkyl optionally substituted with —OH; iii)1-piperidinyl optionally substituted with —C₁₋₄alkyl, —C(O)NH₂,—CO₂C₁₋₄alkyl or —C₀₋₄alkyl-phenyl; iv) piperazinyl optionallysubstituted with —C₁₋₅alkyl, OC₁₋₄alkyl, —C₀₋₄alkylpyridyl, methylpiperidin 4 yl, —C₁₋₄alkylNR_(k)R_(i) or —C₀₋₄alkyl-phenyl, said phenylbeing optionally substituted with one or two R_(T) substituents; whereeach R_(T) substituent is selected from the group consisting of halo,—OCF₃, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CO₂C₁₋₄alkyl, —C(O) C₁₋₄alkyl and—C₀₋₄alkylNR_(k)R_(i), or two R_(T) substituents on adjacent carbonatoms taken together form —O(CH₂)₁₋₂O—; v) phenyl optionally substitutedwith halo, —CF₃, —OCF₃; vi) pyridyl; vii) morpholin-yl; R_(k) is H,—C₁₋₄alkyl or —C(O)₁₋₂C₁₋₄alkyl; R_(i) is H or C₁₋₄alkyl; N-oxides,isomers, enantiomers, racemic mixtures and pharmaceutically acceptablesalts thereof.
 3. The compound according to claim 1 of formula (IB)

wherein: Ar₁ is: i) phenyl substituted with 0, 1, 2 or 3 substituentsR_(a); or ii) a 5- or 6-membered monocyclic aromatic heterocycle ring,optionally substituted with one or two substituents R_(a); where eachR_(a) is independently halo, —C₁₋₄alkyl, —OC₁₋₄alkyl, —CN, —CF₃, —OCF₃,—NO₂, —C(O)C₁₋₄alkyl or —CO₂H; Ar₂ is: i) phenyl substituted with 0, 1,2 or 3 substituents R_(b); where each R_(b) is independently halo,—C₁₋₄alkyl, —C(O)NR_(c)R_(d), —OC₁₋₄alkyl, —OC₁₋₄alkylCF₃, —CN, —CF₃,—OCF₂H, —NO₂, —NR_(c)R_(d), —S(O)₀₋₂C₁₋₄ alkyl, —C(O)C₁₋₄alkyl,S(O)(O)NH₂, —(CH₂)₀₋₂-morpholinyl, piperidin-1yl, piperazinyl, saidpiperazinyl being optionally substituted with a methyl, or two R_(b)substituents on adjacent carbon atoms taken together form —O(CH₂)₁₋₂O—;ii) pyridyl substituted with 0, 1 or 2 substituents R_(e); where eachR_(e) is independently selected from halo, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CF₃, —NR_(c)R_(d) or 4-morpholinyl; or iii) a bicyclic 9-11-memberedaromatic heterocycle optionally substituted with 1 substituent R_(f);where R_(f) is —C₁₋₄alkyl; R_(c) and R_(d) are each independentlyselected from H or —C₁₋₄alkyl; R₁ is H, C₁₋₄alkyl-O—C₁₋₄alkyl, orC₁₋₄alkyl optionally substituted with halo; R₂, R₃, R₄, and R₅ are eachindependently H, halo or —C₁₋₄alkyl; each Y₁, Y₂ and Y₃ is independentlyCH or N; R₆ is i) H, —C₁₋₄alkyl, —CF₃, —OR_(Z) or —NR_(h)R_(i); whereR_(h) is selected from a) H, —C₀₋₄alkylCF₃, —C₁₋₄alkyl-N(CH₃)₂,saturated C₃₋₇cycloalkyl or —C₁₋₄alkyl-monocyclic heteroaryl ring; b)—C₁₋₅alkyl optionally substituted with OH; c)—C₁₋₄alkyl-heterocycloalkyl, wherein said heterocycloalkyl is optionallysubstituted with —C₁₋₄alkyl; or d) —C₀₋₄alkyl-phenyl, said phenyl beingoptionally substituted with one or two R_(j) moieties; where each R_(j)is independently halo, —OC₁₋₄alkyl, Rz is —C₁₋₄alkyl, —C₁₋₄alkylCF₃ or—C₁₋₄alkyl-heterocycloalkyl; ii) 1-pyrrolidinyl optionally substitutedwith a moiety selected from the group consisting of —NR_(k)R_(i) and —C₁alkyl, said —C₁₋₄alkyl optionally substituted with —OH; iii)1-piperidinyl optionally substituted with —C₁₋₄alkyl, —C(O)NH₂,—CO₂C₁₋₄alkyl or —C₀₋₄alkyl-phenyl; iv) piperazinyl optionallysubstituted with -Ci₁₋₅alkyl, —OC₁₋₄alkyl, —C₀₋₄alkylpyridyl,—C₀₋₄alkyl-1-methyl-piperidin-4-yl, —C₀₋₄alkylNR_(k)Ri or—C₀₋₄alkyl-phenyl, said phenyl being optionally substituted with one ortwo R_(T) substituents; where each R_(T) substituent is selected fromthe group consisting of halo, —OCF₃, —C₁₋₄alkyl, —OC₁₋₄alkyl,—CO₂C₁₋₄alkyl, —C(O) C₁₋₄alkyl and —C₀₋₄alkylNR_(k)R_(i), or two R_(T)substituents on adjacent carbon atoms taken together form —O(CH₂)₁₋₂O—;v) phenyl optionally substituted with halo, CF₃; vi) pyridyl; vii)morpholin-yl; R_(k) is H, —C₁₋₄alkyl or —C(O)₁₋₂C₁₋₄alkyl; R_(i) is H orC₁₋₄alkyl; N-oxides, isomers, enantiomers, racemic mixtures andpharmaceutically acceptable salts thereof.
 4. The compound according toclaim 1 wherein each Y_(1 s) Y₂ are CH and Y₃ is N.
 5. The compoundaccording to claim 1 wherein each Y_(1 s) Y₂ and Y₃ are CH.
 6. Thecompound according to claim 4 wherein: Ar₁ is: i) phenyl substitutedwith one substituent R_(a); where R_(a) is halo, or —C₁₋₄alkyl; ii) athienyl ring optionally substituted with one substituents R_(a): whereR_(a) is halo; Ar₂ is: i) phenyl substituted with 1 substituent R_(b);where R_(b) is —OC₀₋₄alkylCF₃; R₁ is H or C₁₋₄ alkyl optionallysubstituted with halo; R₂, R₃, R₄, and R₅ are each independently H, or—C₁₋₄alkyl; R₆ is: i) H; ii) 1-pyrrolidinyl; iii) phenyl optionallysubstituted with —CF₃ or —OCF₃; iv) morpholin-yl.
 7. The compoundaccording to claim 1, selected from:2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-fluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-(methyl(p-tolylsulfonyl)amino)-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamide;2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]prop-2-enamide;N-[[2,6-bis[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]prop-2-enamide;N-[[2,6-bis[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[(4-chlorophenyl)sulfonyl-methyl-amino]prop-2-enamide;(Z)-2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamide;(Z)-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]but-2-enamide;(Z)-2-[(4-chlorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]but-2-enamide;(Z)-2-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]but-2-enamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[(4-chlorophenyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[(4-fluorophenyl)sulfonylamino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;2-[(3,4-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(3-difluorophenyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fluorophenyl)sulfonyl-amino]prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-2-(ethyl(2-thienylsulfonyl)amino)prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-morpholino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;N-[[2-dimethylamino-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-isopropoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-methoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-ethoxy-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;2-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[1-oxido-2-[4-(trifluoromethyl)phenyl]pyridin-1-ium-4-yl]methyl]prop-2-enamide;2-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]prop-2-enamide;2-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]prop-2-enamide;1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethoxy)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[(4-fluorophenyl)sulfonyl-methyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[3-[4-(trifluoromethyl)phenyl]phenyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fluorophenyl)sulfonyl-amino]-N-[[2-pyrrolidin-1-yl-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;1-[ethyl-(4-fiuorophenyl)sulfonyl-amino]-N-[[2-morpholino-6-[4-(trifiuoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide;N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methyl]-2-[ethyl-(4-fiuorophenyl)sulfonyl-amino]prop-2-enamide;N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methy1] cyclopropanecarboxamide;N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]-1-[ethyl-(4-fluorophenyl)sulfonyl-amino]cyclopropanecarboxamide;1-[(5-chloro-2-thienyl)sulfonyl-ethyl-amino]-N-[[2-(4-cyclohexylpiperazin-1-yl)-6-[4-(trifiuoromethyl)phenyl]-4-pyridyl]methyl]cyclopropanecarboxamide.8. Pharmaceutical compositions comprising one or more compounds of claim1 as the active ingredient.
 9. The compounds of claim 1 for use as TRPA1antagonists.
 10. The compounds of claim 1 for use in the treatment ofpain and inflammatory diseases, including airways disorders such asasthma, chronic cough and COPD.
 11. The compound according to claim 2wherein each Y_(1 s) Y₂ are CH and Y₃ is N.
 12. The compound accordingto claim 3 wherein each Y_(1 s) Y₂ are CH and Y₃ is N.
 13. The compoundaccording to claim 2 wherein each Y_(1 s) Y₂ and Y₃ are CH.
 14. Thecompound according to claim 3 wherein each Y_(1 s) Y₂ and Y₃ are CH. 15.The compound according to claim 5 wherein: Ar₁ is: i) phenyl substitutedwith one substituent R_(a); where R_(a) is halo, or —C₁₋₄alkyl; ii) athienyl ring optionally substituted with one substituents R_(a): whereR_(a) is halo; Ar₂ is: i) phenyl substituted with 1 substituent R_(b);where R_(b) is —OC₀₋₄alkylCF₃; R₁ is H or C₁₋₄ alkyl optionallysubstituted with halo; R₂, R₃, R₄, and R₅ are each independently H, or—C₁₋₄alkyl; R₆ is: i) H; ii) 1-pyrrolidinyl; iii) phenyl optionallysubstituted with —CF₃ or —OCF₃; iv) morpholin-yl.